Clinical Trials

To study the safety and feasibility of stereotactic radiation dose escalation following
neoadjuvant chemotherapy with concurrent conventionally fractionated radiation, by
evaluating the acute and late toxicity of treatment.

Stanford is currently not accepting patients for this trial.For more information, please contact Laurie Ann Columbo, (650) 736 - 0792.

Abstract

Nonadherence to assigned treatment jeopardizes the power and interpretability of intent-to-treat comparisons from clinical trial data and continues to be an issue for effectiveness studies, despite their pragmatic emphasis. We posit that new approaches to design need to complement developments in methods for causal inference to address nonadherence, in both experimental and practice settings. This paper considers the conventional study design for psychiatric research and other medical contexts, in which subjects are randomized to treatments that are fixed throughout the trial and presents an alternative that converts the fixed treatments into an adaptive intervention that reflects best practice. The key element is the introduction of an adaptive decision point midway into the study to address a patient's reluctance to remain on treatment before completing a full-length trial of medication. The clinical uncertainty about the appropriate adaptation prompts a second randomization at the new decision point to evaluate relevant options. Additionally, the standard 'all-or-none' principal stratification (PS) framework is applied to the first stage of the design to address treatment discontinuation that occurs too early for a midtrial adaptation. Drawing upon the adaptive intervention features, we develop assumptions to identify the PS causal estimand and to introduce restrictions on outcome distributions to simplify expectation-maximization calculations. We evaluate the performance of the PS setup, with particular attention to the role played by a binary covariate. The results emphasize the importance of collecting covariate data for use in design and analysis. We consider the generality of our approach beyond the setting of psychiatric research.

Abstract

Thirty-eight HLA matched and mismatched patients given combined living donor kidney and enriched CD34(+) hematopoietic cell transplants were enrolled in tolerance protocols using posttransplant conditioning with total lymphoid irradiation and anti-thymocyte globulin. Persistent chimerism for at least 6 months was associated with successful complete withdrawal of immunosuppressive drugs in 16 of 22 matched patients without rejection episodes or kidney disease recurrence with up to 5 years follow up thereafter. One patient is in the midst of withdrawal and five are on maintenance drugs. Persistent mixed chimerism was achieved in some haplotype matched patients for at least 12 months by increasing the dose of T cells and CD34(+) cells infused as compared to matched recipients in a dose escalation study. Success of drug withdrawal in chimeric mismatched patients remains to be determined. None of the 38 patients had kidney graft loss or graft versus host disease with up to 14 years of observation. In conclusion, complete immunosuppressive drug withdrawal could be achieved thus far with the tolerance induction regimen in HLA matched patients with uniform long-term graft survival in all patients.

Abstract

This paper is motivated by a randomized controlled trial to compare an endovascular procedure with conventional medical treatment for stroke patients, in which the endovascular procedure may be effective only in a subgroup of patients. Since the subgroup is not known at the design stage but can be learned statistically from the data collected during the course of the trial, we develop a novel group sequential design that incorporates adaptive choice of the patient subgroup among several possibilities which include the entire patient population as a choice. We define the type I and type II errors of a test in this design and show how a prescribed type I error can be maintained by using the closed testing principle in multiple testing. We also show how asymptotically optimal tests can be constructed by using generalized likelihood ratio statistics for parametric problems and analogous standardized or Studentized statistics for nonparametric tests such as Wilcoxon's rank sum test commonly used for treatment comparison in stroke patients.

Abstract

Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but treatment toxicity has been a barrier to its more widespread use. The nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease (aGVHD), but it has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n = 32), therapy-related myeloid neoplasms (n = 15), MPN (n = 9), and chronic myelomonocytic leukemia (n = 5). The median age of all patients was 63 years (range, 50 to 73). The cumulative incidence of aGVHD grades II to IV was 14% (95% confidence interval [CI], 4% to 23%) and for grades III to IV, 4% (95% CI, 0 to 9%), and it did not differ between patients who received allografts from related or unrelated donors. The cumulative incidence of nonrelapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival and progression-free survival were 41% (95% CI, 29% to 53%) and 35% (95% CI, 23% to 48%), respectively. The safety and tolerability of TLI-ATG, as exemplified by its low NRM, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression.

Abstract

This pilot study aims to provide effect size confidence intervals, clinical trial and intervention feasibility data, and procedural materials for a full-scale randomized controlled trial that will determine the efficacy of Dietary Approaches to Stop Hypertension (DASH) as adjunct therapy to standard care for adults with uncontrolled asthma. The DASH diet encompasses foods (e.g., fresh fruit, vegetables, and nuts) and antioxidant nutrients (e.g., vitamins A, C, E, and zinc) with potential benefits for persons with asthma, but it is unknown whether the whole diet is beneficial. Participants (n=90) will be randomized to receive usual care alone or combined with a DASH intervention consisting of 8 group and 3 individual sessions during the first 3months, followed by at least monthly phone consultations for another 3months. Follow-up assessments will occur at 3 and 6months. The primary outcome measure is the 7-item Juniper Asthma Control Questionnaire, a validated composite measure of daytime and nocturnal symptoms, activity limitations, rescue medication use, and percentage predicted forced expiratory volume in 1second. We will explore changes in inflammatory markers important to asthma pathophysiology (e.g., fractional exhaled nitric oxide) and their potential to mediate the intervention effect on disease control. We will also conduct pre-specified subgroup analyses by genotype (e.g., polymorphisms on the glutathione S transferase gene) and phenotype (e.g., atopy, obesity). By evaluating a dietary pattern approach to improving asthma control, this study could advance the evidence base for refining clinical guidelines and public health recommendations regarding the role of dietary modifications in asthma management.

Abstract

Steroid refractory gastrointestinal (GI) acute graft versus host disease (aGVHD) is a major cause of mortality in hematopoietic stem cell transplantation (HCT) without immune markers to establish a diagnosis or guide therapy. We found that T cell receptor β (TCRβ) CDR3 repertoire sequencing reveals patterns that could eventually serve as a disease biomarker of T cell alloreactivity in aGVHD. We identified T cell clones in GI biopsies in a heterogeneous group of 15 allogeneic HCT patients with GI aGVHD symptoms. Seven steroid-refractory aGVHD patients showed a more conserved TCRβ clonal structure between different biopsy sites in the GI tract than eight primary-therapy responsive patients. Tracking GI clones identified at endoscopy longitudinally in the blood also revealed an increased clonal expansion in patients with steroid-refractory disease. Immune repertoire sequencing-based methods could enable a novel personalized way to guide diagnosis and therapy in diseases where T cell activity is a major determinant.

Abstract

The Diabetes Prevention Program (DPP) lifestyle intervention reduced the incidence of type 2 diabetes mellitus (DM) among high-risk adults by 58%, with weight loss as the dominant predictor. However, it has not been adequately translated into primary care.We evaluated 2 adapted DPP lifestyle interventions among overweight or obese adults who were recruited from 1 primary care clinic and had pre-DM and/or metabolic syndrome. Participants were randomized to (1) a coach-led group intervention (n = 79), (2) a self-directed DVD intervention (n = 81), or (3) usual care (n = 81). During a 3-month intensive intervention phase, the DPP-based behavioral weight-loss curriculum was delivered by lifestyle coach-led small groups or home-based DVD. During the maintenance phase, participants in both interventions received lifestyle change coaching and support remotely-through secure email within an electronic health record system and the American Heart Association Heart360 website for weight and physical activity goal setting and self-monitoring. The primary outcome was change in body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) from baseline to 15 months.At baseline, participants had a mean (SD) age of 52.9 (10.6) years and a mean BMI of 32.0 (5.4); 47% were female; 78%, non-Hispanic white; and 17%, Asian/Pacific Islander. At month 15, the mean ± SE change in BMI from baseline was -2.2 ± 0.3 in the coach-led group vs -0.9 ± 0.3 in the usual care group (P < .001) and -1.6 ± 0.3 in the self-directed group vs usual care (P = .02). The percentages of participants who achieved the 7% DPP-based weight-loss goal were 37.0% (P = .003) and 35.9% (P = .004) in the coach-led and self-directed groups, respectively, vs 14.4% in the usual care group. Both interventions also achieved greater net improvements in waist circumference and fasting plasma glucose level.Proven effective in a primary care setting, the 2 DPP-based lifestyle interventions are readily scalable and exportable with potential for substantial clinical and public health impact.clinicaltrials.gov Identifier: NCT00842426.

Abstract

Although traditional phase II cancer trials are usually single arm, with tumor response as endpoint, and phase III trials are randomized and incorporate interim analyses with progression-free survival or other failure time as endpoint, this paper proposes a new approach that seamlessly expands a randomized phase II study of response rate into a randomized phase III study of time to failure. This approach is based on advances in group sequential designs and joint modeling of the response rate and time to event. The joint modeling is reflected in the primary and secondary objectives of the trial, and the sequential design allows the trial to adapt to increase in information on response and survival patterns during the course of the trial and to stop early either for conclusive evidence on efficacy of the experimental treatment or for the futility in continuing the trial to demonstrate it, on the basis of the data collected so far.

Abstract

The Massachusetts Veterans Epidemiology Research and Information Center in collaboration with the Stanford Center for Innovative Study Design set out to test the feasibility of a new method of evidence generation. The first pilot of a point-of-care clinical trial (POCCT), adding randomization and other study processes to an electronic medical record (EMR) system, was launched to compare the effectiveness of two insulin regimens.Existing functionalities of the Veterans Affairs (VA) computerized patient record system (CPRS)/veterans health information systems and technology architecture (VISTA) were modified to support the activities of a randomized controlled trial including enrolment, randomization, and longitudinal data collection.The VA's CPRS/VISTA was successfully adapted to support the processes of a clinical trial and longitudinal study data are being collected from the medical record automatically. As of 30 June 2011, 55 of the 67 eligible patients approached received a randomized intervention.The design of CPRS/VISTA made integration of study workflows and data collection possible. Institutions and investigators considering similar designs must carefully map clinical workflows and clinical trial workflows to EMR capabilities. POCCT study teams are necessarily interdisciplinary and interdepartmental. As a result, executive sponsorship is critical.POCCT represent a promising new method for conducting clinical science. Much work is needed to understand better the optimal uses and designs for this new approach. Next steps include focus groups to measure patient and clinician perceptions, multisite deployment of the current pilot, and implementation of additional studies.

Abstract

Advances in molecular therapeutics in the past decade have opened up new possibilities for treating cancer patients with personalized therapies, using biomarkers to determine which treatments are most likely to benefit them, but there are difficulties and unresolved issues in the development and validation of biomarker-based personalized therapies. We develop a new clinical trial design to address some of these issues. The goal is to capture the strengths of the frequentist and Bayesian approaches to address this problem in the recent literature and to circumvent their limitations.We use generalized likelihood ratio tests of the intersection null and enriched strategy null hypotheses to derive a novel clinical trial design for the problem of advancing promising biomarker-guided strategies toward eventual validation. We also investigate the usefulness of adaptive randomization (AR) and futility stopping proposed in the recent literature.Simulation studies demonstrate the advantages of testing both the narrowly focused enriched strategy null hypothesis related to validating a proposed strategy and the intersection null hypothesis that can accommodate to a potentially successful strategy. AR and early termination of ineffective treatments offer increased probability of receiving the preferred treatment and better response rates for patients in the trial, at the expense of more complicated inference under small-to-moderate total sample sizes and some reduction in power.The binary response used in the development phase may not be a reliable indicator of treatment benefit on long-term clinical outcomes. In the proposed design, the biomarker-guided strategy (BGS) is not compared to 'standard of care', such as physician's choice that may be informed by patient characteristics. Therefore, a positive result does not imply superiority of the BGS to 'standard of care'. The proposed design and tests are valid asymptotically. Simulations are used to examine small-to-moderate sample properties.Innovative clinical trial designs are needed to address the difficulties and issues in the development and validation of biomarker-based personalized therapies. The article shows the advantages of using likelihood inference and interim analysis to meet the challenges in the sample size needed and in the constantly evolving biomarker landscape and genomic and proteomic technologies.

Abstract

We investigated sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in patients with advanced hematological malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. On the basis of pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. In all, 7 of the 11 patients received BU-containing preparative regimens. Sirolimus was discontinued in three patients because of the toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in one patient because of the risk of poor wound healing. In all, 6 of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post HCT. Two of three patients with grade IV AGVHD had sirolimus discontinued by 9 days post HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were two non-relapse- and two relapse-related deaths. At a median follow-up of 38 months (2-47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of AGVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the BU-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD.

Abstract

We review adaptive designs for clinical trials, giving special attention to the control of the Type I error in late-phase confirmatory trials, when the trial planner wishes to adjust the final sample size of the study in response to an unblinded analysis of interim estimates of treatment effects. We point out that there is considerable inefficiency in using the adaptive designs that employ conditional power calculations to reestimate the sample size and that maintain the Type I error by using certain weighted test statistics. Although these adaptive designs have little advantage over familiar group-sequential designs, our review also describes recent developments in adaptive designs that are both flexible and efficient. We also discuss the use of Bayesian designs, when the context of use demands control over operating characteristics (Type I and II errors) and correction of the bias of estimated treatment effects.

Abstract

Clinical demand for individualized "adaptive" treatment policies in diverse fields has spawned development of clinical trial methodology for their experimental evaluation via multistage designs, building upon methods intended for the analysis of naturalistically observed strategies. Because often there is no need to parametrically smooth multistage trial data (in contrast to observational data for adaptive strategies), it is possible to establish direct connections among different methodological approaches. We show by algebraic proof that the maximum likelihood (ML) and optimal semiparametric (SP) estimators of the population mean of the outcome of a treatment policy and its standard error are equal under certain experimental conditions. This result is used to develop a unified and efficient approach to design and inference for multistage trials of policies that adapt treatment according to discrete responses. We derive a sample size formula expressed in terms of a parametric version of the optimal SP population variance. Nonparametric (sample-based) ML estimation performed well in simulation studies, in terms of achieved power, for scenarios most likely to occur in real studies, even though sample sizes were based on the parametric formula. ML outperformed the SP estimator; differences in achieved power predominately reflected differences in their estimates of the population mean (rather than estimated standard errors). Neither methodology could mitigate the potential for overestimated sample sizes when strong nonlinearity was purposely simulated for certain discrete outcomes; however, such departures from linearity may not be an issue for many clinical contexts that make evaluation of competitive treatment policies meaningful.

Abstract

Clinical trials are widely considered the gold standard in comparative effectiveness research (CER) but the high cost and complexity of traditional trials and concerns about generalizability to broad patient populations and general clinical practice limit their appeal. Unsuccessful implementation of CER results limits the value of even the highest quality trials. Planning for a trial comparing two standard strategies of insulin administration for hospitalized patients led us to develop a new method for a clinical trial designed to be embedded directly into the clinical care setting thereby lowering the cost, increasing the pragmatic nature of the overall trial, strengthening implementation, and creating an integrated environment of research-based care.We describe a novel randomized clinical trial that uses the informatics and statistics infrastructure of the Veterans Affairs Healthcare System (VA) to illustrate one key component (called the point-of-care clinical trial - POC-CT) of a 'learning healthcare system,' and settles a clinical question of interest to the VA.This study is an open-label, randomized trial comparing sliding scale regular insulin to a weight-based regimen for control of hyperglycemia, using the primary outcome length of stay, in non-ICU inpatients within the northeast region of the VA. All non-ICU patients who require in-hospital insulin therapy are eligible for the trial, and the VA's automated systems will be used to assess eligibility and present the possibility of randomization to the clinician at the point of care. Clinicians will indicate their approval for informed consent to be obtained by study staff. Adaptive randomization will assign up to 3000 patients, preferentially to the currently 'winning' strategy, and all care will proceed according to usual practices. Based on a Bayesian stopping rule, the study has acceptable frequentist operating characteristics (Type I error 6%, power 86%) against a 12% reduction of median length of stay from 5 to 4.4 days. The adaptive stopping rule promotes implementation of a successful treatment strategy.Despite clinical equipoise, individual healthcare providers may have strong treatment preferences that jeopardize the success and implementation of the trial design, leading to low rates of randomization. Unblinded treatment assignment may bias results. In addition, generalization of clinical results to other healthcare systems may be limited by differences in patient population. Generalizability of the POC-CT method depends on the level of informatics and statistics infrastructure available to a healthcare system.The methods proposed will demonstrate outcome-based evaluation of control of hyperglycemia in hospitalized veterans. By institutionalizing a process of statistically sound and efficient learning, and by integrating that learning with automatic implementation of best practice, the participating VA Healthcare Systems will accelerate improvements in the effectiveness of care.

Abstract

Secondhand tobacco smoke exposure impairs the control of pediatric asthma. Evidence of the efficacy of interventions to reduce children's exposure and improve disease outcomes has been inconclusive.Caregivers of 519 children aged 3 to 12 years with asthma and reported smoke exposure attended two baseline assessment visits, which involved a parent interview, sampling of the children's urine (for cotinine assay), and spirometry (children?5 years). The caregivers and children (n=352) with significant documented exposure (cotinine?10 ng/mL) attended a basic asthma education session, provided a third urine sample, and were randomized to the Lowering Environmental Tobacco Smoke: LET'S Manage Asthma (LET'S) intervention (n=178) or usual care (n=174). LET'S included three in-person, stage-of-change-based counseling sessions plus three follow-up phone calls. Cotinine feedback was given at each in-person session. Follow-up visits at 6 and 12 months postrandomization repeated the baseline data collection. Multivariate regression analyses estimated the intervention effect on the natural logarithm of the cotinine to creatinine ratio (lnCCR), use of health-care services, and other outcomes.In the sample overall, the children in the LET'S intervention had lower follow-up lnCCR values compared with the children in usual care, but the group difference was not significant (? coefficient=-0.307, P=.064), and there was no group difference in the odds of having>one asthma-related medical visit (? coefficient=0.035, P=.78). However, children with high-risk asthma had statistically lower follow-up lnCCR values compared with children in usual care (? coefficient=-1.068, P=.006).The LET'S intervention was not associated with a statistically significant reduction in tobacco smoke exposure or use of health-care services in the sample as a whole. However, it appeared effective in reducing exposure in children at high risk for subsequent exacerbations. Trial registry: ClinicialTrials.gov; No.: NCT00217958; URL: clinicaltrials.gov.

Abstract

Minimizing the imbalance of key baseline covariates between treatments is known to be very important to the precision of the estimate of treatment effect in clinical research. Dynamic randomization allocation techniques have been used to achieve balance across multiple baseline characteristics. However, empirical data are limited on how these techniques compare in terms of balance and efficiency. We are motivated by a newly funded randomized controlled trial, in which we have the option of choosing between two methods of randomization at the subject level: (1) randomizing individual subjects consecutively as they are enrolled, using Pocock and Simon's minimization method, and (2) simultaneously randomizing blocks of subjects once all subjects in a block have been enrolled, using a balance algorithm originally developed for cluster randomized trials.To compare dynamic block randomization and minimization in terms of balance on baseline covariates and statistical efficiency. Simple randomization was included as a reference.A simulation study using data from a previous randomized controlled trial was conducted to compare balance statistics and the accuracy and power of hypothesis testing among the randomization methods.Dynamic block randomization consistently produced the best balance and highest power for various sample and treatment effect sizes, even after post-adjustment of the pre-specified baseline covariates in all three methods. Consistent with previous reports, minimization performed better in balance and power than simple randomization; however, the differences were noticeably smaller compared to those between dynamic block randomization and simple randomization.In this simulation study, we considered three sample sizes and two block sizes for a two-arm randomized trial. We assumed no interactions among the multiple baseline covariates. It is necessary to evaluate how the results may vary when the simulation conditions are changed before drawing broader conclusions regarding comparisons between the randomization methods.This study demonstrates that dynamic block randomization outperforms minimization with regard to achieving balance and maximizing efficiency. Nevertheless, the differences across the three randomization strategies are modest. The statistical advantages associated with dynamic block randomization need to be considered in relation to the planned sample size and the practical issues for its implementation in deciding the preferred method of randomization for a given trial (e.g., the time required to accrue blocks of subjects of adequate size as balanced against the need to commence intervention/treatment immediately in those randomized to that experimental condition).

Abstract

The prostate cancer risk calculator from the Prostate Cancer Prevention Trial estimates the risk of positive biopsy and 1 containing high grade disease (Gleason score 7 or greater) based on prostate specific antigen, digital rectal examination, family history, race and prior negative biopsy. Since data used to create the calculator came from an unreferred population that underwent mainly sextant biopsy, to our knowledge its usefulness in the contemporary urology practice is unknown.We performed the same multivariate logistic regression used to derive the prostate cancer risk calculator in a cohort of men from the Stanford Prostate Needle Biopsy Database who underwent initial prostate needle biopsy using an extended 12-core scheme.Our predictions of overall prostate cancer risk did not differ significantly from those of the calculator. Prostate specific antigen, abnormal digital rectal examination and family history were independent risk factors. However, our model predicted a much greater risk of high grade disease than the prostate cancer risk calculator. Prostate specific antigen, abnormal digital rectal examination and age were independent risk factors for high grade disease.The difference between our estimated risk of high grade prostate cancer and that of the prostate cancer risk calculator can be potentially explained by 1) differences between the cohorts (referred vs unreferred) or 2) the difference in grading, ie grading accuracy due to the difference in biopsy schemes or to temporally related grade shifts. Caution should be used when applying the prostate cancer risk calculator to counsel patients referred for suspicion of prostate cancer since it underestimates the risk of high grade disease.

Abstract

Sequential multiple assignment randomized (SMAR) designs are used to evaluate treatment policies, also known as adaptive treatment strategies (ATS). The determination of SMAR sample sizes is challenging because of the sequential and adaptive nature of ATS, and the multi-stage randomized assignment used to evaluate them.We derive sample size formulae appropriate for the nested structure of successive SMAR randomizations. This nesting gives rise to ATS that have overlapping data, and hence between-strategy covariance. We focus on the case when covariance is substantial enough to reduce sample size through improved inferential efficiency.Our design calculations draw upon two distinct methodologies for SMAR trials, using the equality of the optimal semi-parametric and Bayesian predictive estimators of standard error. This 'hybrid' approach produces a generalization of the t-test power calculation that is carried out in terms of effect size and regression quantities familiar to the trialist.Simulation studies support the reasonableness of underlying assumptions as well as the adequacy of the approximation to between-strategy covariance when it is substantial. Investigation of the sensitivity of formulae to misspecification shows that the greatest influence is due to changes in effect size, which is an a priori clinical judgment on the part of the trialist.We have restricted simulation investigation to SMAR studies of two and three stages, although the methods are fully general in that they apply to 'K-stage' trials.Practical guidance is needed to allow the trialist to size a SMAR design using the derived methods. To this end, we define ATS to be 'distinct' when they differ by at least the (minimal) size of effect deemed to be clinically relevant. Simulation results suggest that the number of subjects needed to distinguish distinct strategies will be significantly reduced by adjustment for covariance only when small effects are of interest.

Abstract

Bevacizumab improves responses and progression-free survival when added to first-line paclitaxel/carboplatin or cisplatin/gemcitabine for patients with advanced nonsquamous non-small cell lung cancer. This study was designed to evaluate toxicities and efficacy of gemcitabine/carboplatin/bevacizumab.Patients with untreated advanced nonsquamous non-small cell lung cancer, with no evidence of brain metastases and not on anticoagulation were eligible. Patients received gemcitabine 1000 mg/m on days 1 and 8; carboplatin area under the curve 5 day 1; and bevacizumab 15 mg/kg day 1 every 3 weeks for up to six cycles. Bevacizumab was then continued every 3 weeks until disease progression or unacceptable toxicity.From July 2006 to December 2008, 48 patients were enrolled: 23 (48%) men, 25 (52%) women, and 19 (40%) never smokers. One patient never received therapy and is not included in the analysis. Median cycle number was 8 (1-42) with 37 patients (78.7%) completing ?4 cycles of three drugs. Dose reductions occurred in 34 (72.3%) patients. Grade 3/4 toxicities included neutropenia (47%/15%), thrombocytopenia (11%/15%), anemia (6%/0%), dyspnea (6%/2%), bacterial pneumonia (4%/0%), and hypertension (4%/2%). No neutropenic fevers occurred. One patient died of hemoptysis. Grade 3 bleeding occurred in three other patients. There were seven (14.9%) partial responses. Median time to first event (progression/death/toxicity requiring discontinuation) was 6.4 months (95% confidence interval: 4.8-7.9 months). The median overall survival (OS) was 12.8 months (95% confidence interval: 10.0-16.5). The OS is 57% at 1 year and 10% at 2 years.Although perhaps skewed by a high proportion of nonsmokers and women, treatment with gemcitabine/carboplatin/bevacizumab has an acceptable toxicity profile with promising median OS despite a low response rate.

Abstract

Warfarin anticoagulation reduces thromboembolic complications in patients with atrial fibrillation or mechanical heart valves, but effective management is complex, and the international normalized ratio (INR) is often outside the target range. As compared with venous plasma testing, point-of-care INR measuring devices allow greater testing frequency and patient involvement and may improve clinical outcomes.We randomly assigned 2922 patients who were taking warfarin because of mechanical heart valves or atrial fibrillation and who were competent in the use of point-of-care INR devices to either weekly self-testing at home or monthly high-quality testing in a clinic. The primary end point was the time to a first major event (stroke, major bleeding episode, or death).The patients were followed for 2.0 to 4.75 years, for a total of 8730 patient-years of follow-up. The time to the first primary event was not significantly longer in the self-testing group than in the clinic-testing group (hazard ratio, 0.88; 95% confidence interval, 0.75 to 1.04; P=0.14). The two groups had similar rates of clinical outcomes except that the self-testing group reported more minor bleeding episodes. Over the entire follow-up period, the self-testing group had a small but significant improvement in the percentage of time during which the INR was within the target range (absolute difference between groups, 3.8 percentage points; P<0.001). At 2 years of follow-up, the self-testing group also had a small but significant improvement in patient satisfaction with anticoagulation therapy (P=0.002) and quality of life (P<0.001).As compared with monthly high-quality clinic testing, weekly self-testing did not delay the time to a first stroke, major bleeding episode, or death to the extent suggested by prior studies. These results do not support the superiority of self-testing over clinic testing in reducing the risk of stroke, major bleeding episode, and death among patients taking warfarin therapy. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT00032591.).

Abstract

Autologous hematopoietic cell transplantation with augmented BCNU regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL); however, BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m(2), and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had 1 or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pretransplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9%-24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n = 24), 1 (n = 37), 2 (n = 23), or 3 (n = 8) risk factors, respectively. Regression analysis identified PET status pretransplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted.

Abstract

Rituximab has been given after autologous hematopoietic cell transplantation for recurrent or refractory B-cell lymphoma with the goal of eradicating minimal residual disease. Our previous report showed that administration of two courses of rituximab after transplantation is feasible, with encouraging clinical outcomes after a short follow-up. However, neutropenia after the first or second post-transplantation rituximab treatment occurred in 52% of patients. We previously reported that polymorphisms of two immunoglobulin G Fc receptors predict rituximab response, presumably because of their role in antibody-dependent cellular cytotoxicity. In the current report, we determine whether FcgammaR polymorphisms are correlated with clinical outcomes in 33 patients with B-cell non-Hodgkin's lymphoma who received post-transplantation rituximab.Genomic DNA was used for FcgammaRIIIa V/F or the FcgammaRIIa H/R genotyping. The FcgammaR polymorphisms were then correlated with the incidence of rituximab-induced neutropenia, event-free survival (EFS), and overall survival (OS).The FcgammaRIIIa 158 V allele dose was correlated with a higher incidence of rituximab-induced neutropenia. The odds of neutropenia after the first or second post-transplantation rituximab increased three-fold with each V allele (robust z = 2.08, P = .038). The FcgammaRIIa polymorphism had no impact on rituximab-induced neutropenia. We did not observe a correlation of either FcgammaRIIIa or FcgammaRIIa polymorphism with EFS or OS.The high affinity FcgammaRIIIa 158 V allele is associated with rituximab-induced neutropenia after autologous transplantation. This is a potential tool to identify a high-risk population for developing neutropenia after antibody therapy.

Abstract

Obesity and asthma have reached epidemic proportions in the US. Their concurrent rise over the last 30 years suggests that they may be connected. Numerous observational studies support a temporally-correct, dose-response relationship between body mass index (BMI) and incident asthma. Weight loss, either induced by surgery or caloric restriction, has been reported to improve asthma symptoms and lung function. Due to methodological shortcomings of previous studies, however, well-controlled trials are needed to investigate the efficacy of weight loss strategies to improve asthma control in obese individuals.BE WELL is a 2-arm parallel randomized clinical trial (RCT) of the efficacy of an evidence-based, comprehensive, behavioral weight loss intervention, focusing on diet, physical activity, and behavioral therapy, as adjunct therapy to usual care in the management of asthma in obese adults. Trial participants (n = 324) are patients aged 18 to 70 years who have suboptimally controlled, persistent asthma, BMI between 30.0 and 44.9 kg/m2, and who do not have serious comorbidities (e.g., diabetes, heart disease, stroke). The 12-month weight loss intervention to be studied is based on the principles of the highly successful Diabetes Prevention Program lifestyle intervention. Intervention participants will attend 13 weekly group sessions over a four-month period, followed by two monthly individual sessions, and will then receive individualized counseling primarily by phone, at least bi-monthly, for the remainder of the intervention. Follow-up assessment will occur at six and 12 months. The primary outcome variable is the overall score on the Juniper Asthma Control Questionnaire measured at 12 months. Secondary outcomes include lung function, asthma-specific and general quality of life, asthma medication use, asthma-related and total health care utilization. Potential mediators (e.g., weight loss and change in physical activity level and nutrient intake) and moderators (e.g., socio-demographic characteristics and comorbidities) of the intervention effects also will be examined.This RCT holds considerable potential for illuminating the nature of the obesity-asthma relationship and advancing current guidelines for treating obese adults with asthma, which may lead to reduced morbidity and mortality related to the comorbidity of the two disorders.NCT00901095.

Abstract

The survival outlook in advanced mycosis fungoides (MF) is poor. Autologous and allogeneic stem cell transplants (SCT) have been shown, in small case series and case reports, to have the potential for long-term remission or to alter disease course. Allogeneic SCT is thought to have a curative potential secondary to a graft-versus-lymphoma (GVL) effect. A patient-level meta-analysis was performed to compare the outcome of allogeneic versus autologous SCT in patients with MF/Sézary syndrome (SS) using 39 cases from the literature. There were a total of 20 allogeneic and 19 autologous transplant cases. The gender, age, and stage distribution was similar between the transplant groups. The allogeneic group received significantly more systemic therapies prior to transplant (P < .0005) and had longer follow-up after transplant. Overall survival (OS) results showed a more favorable outcome of patients who received allogeneic SCT (P = .027). Event-free survival (EFS) demonstrated a more durable response in patients who received allogeneic SCT (P = .002). In the allogeneic group, the majority (70%) of patients experienced persistent graft-versus-host disease (GVHD), mostly with mild to moderate severity, and 2 of 4 deaths were related to GVHD. Meanwhile, the majority of the deaths (8 of 10) in the autologous group were because of progressive disease. These results support the belief that allogeneic SCT offers a better survival and disease-free outcome versus autologous SCT in MF/SS, likely because of a GVL effect.

Abstract

A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.

Abstract

In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects.This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure-specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (-20%), low-density lipoprotein cholesterol (-30%), and body weight (-11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen.DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.

Abstract

Phase III clinical trials for depression enroll participants with major depressive disorder according to stringent inclusion and exclusion criteria. These patients may not be representative of typical depressed patients seeking treatment. This analysis used data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project--which used broad inclusion and minimal exclusion criteria--to evaluate whether phase III clinical trials recruit representative depressed outpatients.Of 2,855 participants, 22.2% met typical entry criteria for phase III clinical trials (efficacy sample) and 77.8% did not (nonefficacy sample). These groups were compared regarding baseline sociodemographic and clinical features and the characteristics and outcomes of acute-phase treatment.The efficacy sample had a shorter average duration of illness and lower rates of family history of substance abuse, prior suicide attempts, and anxious and atypical symptom features. Despite similar medication dosing and time at exit dose, the efficacy participants tolerated citalopram better. They also had higher rates of response (51.6% versus 39.1%) and remission (34.4% versus 24.7%). These differences persisted even after adjustments for baseline differences.Phase III trials do not recruit representative treatment-seeking depressed patients. Broader phase III inclusion criteria would increase the generalizability of results to practice, potentially reducing placebo response and remission rates (reducing the risk of failed trials) but at the risk of some increase in adverse events.

Abstract

Abnormalities in the gene regulating methylenetetrahydrofolate reductase (MTHFR) are associated with increased homocysteine levels and increased mortality in normal and chronic kidney disease (CKD) populations.Gene association study.This was a substudy of 677 patients from 21 Veterans Affairs medical centers participating in a randomized clinical trial (Homocysteinemia in Kidney and End-Stage Renal Disease [HOST]) of the effect on all-cause mortality of vitamin-induced lowering of plasma homocysteine levels. Of 677 patients, 213 (31%) were treated by using dialysis (end-stage renal disease [ESRD]) and 464 (69%) had a Cockcroft-Gault estimated creatinine clearance less than 30 mL/min (advanced CKD).Polymorphisms C677T (rs1801133) and A1298C (rs1801131) of the MTHFR gene.Unadjusted and adjusted all-cause mortality.DNA was extracted from blood samples and amplified by means of polymerase chain reaction.The adjusted hazard ratio in a recessive model of the relationship between the C677T polymorphism and all-cause mortality in all patients was 1.47 (95% confidence interval, 1.00 to 2.16; P = 0.05). In patients with ESRD with the mutant TT genotype, the adjusted hazard ratio for mortality in all patients was 2.27 (95% confidence interval, 1.07 to 4.84; P = 0.03); patients with advanced CKD showed a similar, although not significant, trend. The risk of myocardial infarction (P = 0.05) and composite risk of myocardial infarction, stroke, lower-extremity amputation, and mortality (P = 0.02) were greater in patients with ESRD with the mutant T allele at nucleotide 677. The overall relationship between the A1298C polymorphism and mortality was not significant (P = 0.6).Participants were 98% men; DNA samples were not obtained at enrollment in HOST; linkage disequilibrium with another causal polymorphism is a potential confounding factor; and power was reduced by the limited number of participants.These findings provide additional support for the hypothesis that the mutant TT genotype at nucleotide 677 of the gene regulating MTHFR activity may increase the mortality risk in patients with ESRD.

Abstract

Beta-blocker therapy has become a mainstay therapy for the over 5 million patients with chronic heart failure in the United States. Variation in clinical response to beta-blockers is a well-known phenomenon and may be because of genetic differences between patients. We hypothesized that variation in genes of the endothelin system mediate the clinical response to beta-blockers in heart failure.Single nucleotide polymorphisms (SNPs) in six endothelin system genes were genotyped in 309 heart failure patients in a randomized trial of bucindolol versus placebo therapy. We adjusted for multiple comparisons and tested for association between genotype and time to two prospective endpoints.Nine SNPs were sufficiently common to undergo statistical analysis. The SNPs had no significant effect on prospective outcomes in the placebo group, or on the primary endpoint of time to death in either arm. Two SNPs (IVS-4 G/A and Lys198Asn) in the endothelin-1 gene, however, predicted time to the combined endpoint of heart failure hospitalization or all-cause death in bucindolol-treated patients. The alleles at these SNPs were in tight linkage disequilibrium appearing on either of two complementary haplotypes. A 'dose-response' trend was observed, with participants carrying the rarer haplotype having the highest hazard ratios as compared to the relative 'protective' effect of the common haplotype.A common endothelin-1 gene haplotype may be a pharmacogenetic predictor of a favorable clinical response to beta-blocker therapy in heart failure patients. The existence of a less common 'high-risk' haplotype could identify a subpopulation of heart failure patients destined to respond poorly to beta-blocker therapies.

Abstract

Longitudinal designs in psychiatric research have many benefits, including the ability to measure the course of a disease over time. However, measuring participants repeatedly over time also leads to repeated opportunities for missing data, either through failure to answer certain items, missed assessments, or permanent withdrawal from the study. To avoid bias and loss of information, one should take missing values into account in the analysis. Several popular ways that are now being used to handle missing data, such as the last observation carried forward (LOCF), often lead to incorrect analyses. We discuss a number of these popular but unprincipled methods and describe modern approaches to classifying and analyzing data with missing values. We illustrate these approaches using data from the WECare study, a longitudinal randomized treatment study of low income women with depression.

Abstract

Excess iron has been implicated in cancer risk through increased iron-catalyzed free radical-mediated oxidative stress.A multicenter randomized, controlled, single-blinded clinical trial (VA Cooperative Study #410) tested the hypothesis that reducing iron stores by phlebotomy would influence vascular outcomes in patients with peripheral arterial disease. Patients without a visceral malignancy in the last 5 years (n = 1277) were randomly assigned to control (n = 641) or iron reduction (n = 636). Occurrence of new visceral malignancy and cause-specific mortality data were collected prospectively. Cancer and mortality outcomes in the two arms were compared using intent-to-treat analysis with a Cox proportional hazards regression model. Statistical tests were two-sided.Patients were followed up for an average of 4.5 years. Ferritin levels were similar in both groups at baseline but were lower in iron reduction patients than control patients across all 6-month visits (mean = 79.7 ng/mL, 95% confidence interval [CI] = 73.8 to 85.5 ng/mL vs 122.5 ng/mL, 95% CI = 115.5 to 129.5 ng/mL; P < .001). Risk of new visceral malignancy was lower in the iron reduction group than in the control group (38 vs 60, hazard ratio [HR] = 0.65, 95% CI = 0.43 to 0.97; P = .036), and, among patients with new cancers, those in the iron reduction group had lower cancer-specific and all-cause mortality (HR = 0.39, 95% CI = 0.21 to 0.72; P = .003; and HR = 0.49, 95% CI = 0.29 to 0.83; P = .009, respectively) than those in the control group. Mean ferritin levels across all 6-monthly visits were similar in patients in the iron reduction and control groups who developed cancer but were lower among all patients who did not develop cancer than among those who did (76.4 ng/mL, 95% CI = 71.4 to 81.4 ng/mL, vs 127.1 ng/mL, 95% CI = 71.2 to 183.0 ng/mL; P = .017).Iron reduction was associated with lower cancer risk and mortality. Further studies are needed to define the role of body iron in cancer risk.

Abstract

Secondhand smoke triggers childhood asthma. Understanding sources of exposure, parental beliefs about exposure, and readiness to change that exposure are important for designing smoke exposure reduction interventions.As part of screening for a clinical trial of a smoke exposure reduction intervention, 519 smoke-exposed children 3 to 12 years old with asthma provided urine specimens for cotinine testing, and their primary caregivers completed questionnaires.The urine cotinine to creatinine ratio (CCR) was lowest if neither the primary caregiver nor day-care provider smoked (mean CCR, 14.0; SD, 14.4), greater if either smoked (mean CCR, 22.2; SD, 21.3; and mean, CCR, 26.3; SD, 22.2, respectively), and greatest if both smoked (mean CCR, 39.6; SD, 27.5; p < 0.01). Parental perception of their child's exposure was weakly associated with the child's CCR (r(2) = 0.11, p < 0.001). Most parents (58.3%) reported that tobacco smoke exposure had small/no negative effect on their child's asthma. Substantial proportions of those for whom a specific exposure reduction action was relevant were classified as contemplating, preparing, or had recently taken action to reduce their child's exposure, including smoking cessation (61.3%), keeping the child out of smoke-exposed places (72.7%), and making the child's home (49.2%) and areas out of the home smoke free (66.9%).Smoking by the primary caregiver and day-care provider are important sources of exposure for children with asthma. Parental assessment of their child's exposure is associated with biologically confirmed exposure but cannot be relied on to assess that exposure. Although the harm of smoke exposure was frequently underestimated, many parents appeared receptive to considering action to reduce their child's exposure.(Clinicaltrials.gov). Identifier: NCT00217958.

Abstract

Clinical trials that randomize subjects to decision algorithms, which adapt treatments over time according to individual response, have gained considerable interest as investigators seek designs that directly inform clinical decision making. We consider designs in which subjects are randomized sequentially at decision points, among adaptive treatment options under evaluation. We present a sequential method to estimate the comparative effects of the randomized adaptive treatments, which are formalized as adaptive treatment strategies. Our causal estimators are derived using Bayesian predictive inference. We use analytical and empirical calculations to compare the predictive estimators to (i) the 'standard' approach that allocates the sequentially obtained data to separate strategy-specific groups as would arise from randomizing subjects at baseline; (ii) the semi-parametric approach of marginal mean models that, under appropriate experimental conditions, provides the same sequential estimator of causal differences as the proposed approach. Simulation studies demonstrate that sequential causal inference offers substantial efficiency gains over the standard approach to comparing treatments, because the predictive estimators can take advantage of the monotone structure of shared data among adaptive strategies. We further demonstrate that the semi-parametric asymptotic variances, which are marginal 'one-step' estimators, may exhibit significant bias, in contrast to the predictive variances. We show that the conditions under which the sequential method is attractive relative to the other two approaches are those most likely to occur in real studies.

Abstract

An adaptive treatment strategy (ATS) is a rule for adapting a treatment plan to a patient's history of previous treatments and the response to those treatments. The ongoing management of chronic disease defines an ATS, which may be implicit and hidden or explicit and well-specified. The ATS is characterized by the use of intermediate, early markers of response to dynamically alter treatment decisions, in order to achieve a favorable ultimate outcome. We illustrate the ATS concept and describe how the effect of initial treatment decisions depends on the performance of subsequent decisions at later stages. We show how to compare two or more ATSs, or to determine an optimal ATS, using a sequential multiple assignment randomized (SMAR) trial. Designers of clinical trials might find the ATS concept useful in improving the efficiency and ecological relevance of clinical trials.

Abstract

Decisions concerning treatment changes pervade the management of chronic psychiatric disorders that resist definitive cure, yet empirical evidence for the comparative clinical effectiveness of treatment strategies remains underdeveloped. In this paper we exploit the example of psychosis following substance use to illustrate some new developments in clinical trials design that can provide the most solid evidence base for defining successful strategies. The intent is to explore the strengths and limitations of the methodological approach through a meaningful clinical example, with an emphasis on concepts and issues. Both methodology and clinical science are overviewed.

Abstract

In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging.We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV).The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS.In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

Abstract

In vivo analyses of thymopoiesis in mice defective in signaling through Kit and gammac or Kit and IL-7Ralpha demonstrate synergy and partial complementation of gammac or IL-7-mediated signaling by the Kit signaling pathway. Our molecular analysis in T-lymphoid cells as well as in nonhematopoietic cells shows that Kit and IL-7R signaling pathways directly interact. KL-mediated activation of Kit induced strong tyrosine phosphorylation of gammac and IL-7Ralpha in the absence of IL-7. Activated Kit formed a complex with either IL-7Ralpha or gammac, and tyrosine phosphorylation of both subunits occurred independently of Jak3, suggesting that gammac and IL-7Ralpha are each direct substrates of Kit. Kit activated Jak3 in an IL-7R-dependent manner. Moreover, deficient Stat5 activation of the Kit mutant YY567/569FF lacking intrinsic Src activation capacity was partially reconstituted in the presence of IL-7R and Jak3. Based on the molecular data, we propose a model of Kit-mediated functional activation of gammac-containing receptors such as IL-7R, similar to the interaction between Kit and Epo-R. Such indirect activation of the Jak-Stat pathway induced by the interaction between an RTK and type I cytokine receptor could be the underlying mechanism for a context-specific signaling repertoire of a pleiotropic RTK-like Kit.

Abstract

To investigate the expression pattern of hypoxia-induced proteins identified as being involved in malignant progression of head-and-neck squamous cell carcinoma (HNSCC) and to determine their relationship to tumor pO(2) and prognosis.We performed immunohistochemical staining of hypoxia-induced proteins (carbonic anhydrase IX [CA IX], BNIP3L, connective tissue growth factor, osteopontin, ephrin A1, hypoxia inducible gene-2, dihydrofolate reductase, galectin-1, IkappaB kinase beta, and lysyl oxidase) on tumor tissue arrays of 101 HNSCC patients with pretreatment pO(2) measurements. Analysis of variance and Fisher's exact tests were used to evaluate the relationship between marker expression, tumor pO(2), and CA IX staining. Cox proportional hazard model and log-rank tests were used to determine the relationship between markers and prognosis.Osteopontin expression correlated with tumor pO(2) (Eppendorf measurements) (p = 0.04). However, there was a strong correlation between lysyl oxidase, ephrin A1, and galectin-1 and CA IX staining. These markers also predicted for cancer-specific survival and overall survival on univariate analysis. A hypoxia score of 0-5 was assigned to each patient, on the basis of the presence of strong staining for these markers, whereby a higher score signifies increased marker expression. On multivariate analysis, increasing hypoxia score was an independent prognostic factor for cancer-specific survival (p = 0.015) and was borderline significant for overall survival (p = 0.057) when adjusted for other independent predictors of outcomes (hemoglobin and age).We identified a panel of hypoxia-related tissue markers that correlates with treatment outcomes in HNSCC. Validation of these markers will be needed to determine their utility in identifying patients for hypoxia-targeted therapy.

Abstract

To correlate [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen.We analyzed retrospectively 81 patients with Hodgkin's disease who had serial [(18)F]FDG-PET scans performed at baseline and again at the completion of Stanford V chemotherapy, before planned radiotherapy. Patients with favorable stage I/II (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were scanned after 8 and 12 weeks of chemotherapy, respectively. Radiotherapy fields were determined before starting chemotherapy based on baseline computed tomography scans.After chemotherapy, six of 81 patients had residual [(18)F]FDG-PET-positive sites, all in sites for which radiotherapy was planned. Four of the six patients with positive [(18)F]FDG-PET scans after chemotherapy experienced relapse compared with just three of 75 patients with negative [(18)F]FDG-PET scans. At a median follow-up of 4 years, the freedom from progression (FFP) was 96% in postchemotherapy [(18)F]FDG-PET-negative patients versus 33% in [(18)F]FDG-PET-positive patients (P < .0003). In a bivariate Cox model, [(18)F]FDG-PET positivity after chemotherapy remained a highly significant predictor of progression-free survival even after controlling for bulky disease and International Prognostic Score more than 2.These data indicate that PET status after chemotherapy is strongly predictive of FFP with the Stanford V regimen despite the use of consolidative radiotherapy. These results have implications for the design of clinical trials adapted to functional imaging.

Abstract

Ethical aspects of prevention trials, as they differ from therapeutic trials, have not been fully explored. This article aims to define and demonstrate the existence of "preventive misconception" (PM), a misunderstanding in which research participants in prevention trials make an "overestimate in probability or level of personal protection that is afforded by being enrolled in a trial of a preventive intervention."A rating tool was developed to evaluate PM, using data collected between August 2000 and July 2002 as part of a nationwide study of the quality of informed consent in a trial of a shingles vaccine. During 2005-2006, two pair of raters assessed the responses of 50 participants to questions asked after the participants had given consent to participate in the shingles trial. Two pair of raters evaluated the response for the presence and type of PM. Each pair of raters adjudicated their responses and inter-rater reliability was assessed.Adjudicated pairs of raters agreed that 32% (CI: 20.7%-45.9%) of participants showed evidence of PM (kappa=0.71, CI: 0.52-0.90); that 12% (CI: 5.2%-24.2%) of participants underestimated the probability of receiving placebo (kappa=0.53, CI: 0.24-0.83); and that 24% (CI: 14.2%-37.6%) overestimated the likely personal effectiveness of the experimental intervention (kappa=0.42, CI: 0.08-0.76).This study newly describes the concept of preventive misconception and empirically demonstrates its existence in trials of prevention. Study participants may overestimate the protection that they receive by being enrolled in a trial of prevention, which poses ethical challenges for research.

Abstract

Treatment of major depressive disorder typically entails implementing treatments in a stepwise fashion until a satisfactory outcome is achieved. This study sought to identify factors that affect patients' willingness to accept different second-step treatment approaches.Participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who had unsatisfactory outcomes after initial treatment with citalopram were eligible for a randomized second-step treatment trial. An equipoise-stratified design allowed participants to exclude or include specific treatment strategies. Analyses were conducted to identify factors associated with the acceptability of the following second-step treatments: cognitive therapy versus no cognitive therapy, any switch strategy versus any augmentation strategy (including cognitive therapy), and a medication switch strategy only versus a medication augmentation strategy only.Of the 1,439 participants who entered second-step treatment, 1% accepted all treatment strategies, 3% accepted only cognitive therapy, and 26% accepted cognitive therapy (thus, 71% did not accept cognitive therapy). Those with higher educational levels or a family history of a mood disorder were more likely to accept cognitive therapy. Participants in primary care settings and those who experienced a greater side effect burden or a lower reduction in symptom severity with citalopram were more likely to accept a switch strategy as compared with an augmentation strategy. Those with concurrent drug abuse and recurrent major depressive disorder were less likely to accept a switch strategy.Few participants accepted all treatments. Acceptance of cognitive therapy was primarily associated with sociodemographic characteristics, while acceptance of a treatment switch was associated with the results of the initial treatment.

Abstract

The conduct of trials in children is beset with special difficulties associated with the dearth of treatment data, the considerable heterogeneity of pediatric patient populations connected with (for example) developmental stage, and the strong desire of parents to see that children are provided with the best possible care at all times. To address these issues, we propose the adaptive treatment strategy (ATS) study in which medication changes are adaptively determined according to the evolving treatment response of the individual child. To formalize this methodological approach, we parameterize an ATS as a "threshold" decision rule that monitors whether the patient's response trajectory crosses some threshold of failure. In this formulation, the threshold represents a priori judgments about when to give up on response to medication, and the goal is to find the right response thresholds for continuation, augmentation, or switching. Our exposition is developed in the specific clinical context of childhood mania to maximize accessibility of the ideas but applies more generally to other chronic mental and physical health disorders that are difficult to treat.

Abstract

Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in dilated cardiomyopathy (DCM) without skeletal muscle disease is not known.Denaturing high-performance liquid chromatography was used to screen DES for mutations in 116 DCM families from the Familial Dilated Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects on cytoskeletal desmin network architecture were analyzed with confocal microscopy. Five novel missense DES mutations, including the first localized to the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection of DES mutations in the 2B domain severely disrupted the fine intracytoplasmic staining of desmin, causing clumping of the desmin protein. A tail domain mutation (Val459Ile) showed milder effects on desmin cytoplasmic network formation and appears to be a low-penetrant mutation restricted to black subjects.The prevalence of DES mutations in DCM is between 1% and 2%, and mutations in the 1A helical domain, as well as the 2B rod domain, are capable of causing a DCM phenotype. The lack of severe disruption of cytoskeletal desmin network formation seen with mutations in the 1A and tail domains suggests that dysfunction of seemingly intact desmin networks is sufficient to cause DCM.

Abstract

To evaluate a new alcohol-related risk score for research use.Using data from a previously reported trial of a screening and education system for older adults (Computerized Alcohol-Related Problems Survey), secondary analyses were conducted comparing the ability of two different measures of risk to detect post-intervention group differences: the original categorical outcome measure and a new, finely grained quantitative risk score based on the same research-based risk factors.Three primary care group practices in southern California.Six hundred sixty-five patients aged 65 and older.A previously calculated, three-level categorical classification of alcohol-related risk and a newly developed quantitative risk score.Mean post-intervention risk scores differed between the three experimental conditions: usual care, patient report, and combined report (P

Abstract

Accumulation of iron in excess of physiologic requirements has been implicated in risk of cardiovascular disease because of increased iron-catalyzed free radical-mediated oxidative stress.To test the hypothesis that reducing body iron stores through phlebotomy will influence clinical outcomes in a cohort of patients with symptomatic peripheral arterial disease (PAD). Design, Setting, andMulticenter, randomized, controlled, single-blinded clinical trial based on the Iron (Fe) and Atherosclerosis Study (FeAST) (VA Cooperative Study #410) and conducted between May 1, 1999, and April 30, 2005, within the Department of Veterans Affairs Cooperative Studies Program and enrolling 1277 patients with symptomatic but stable PAD. Those with conditions likely to cause acute-phase increase of the ferritin level or with a diagnosis of visceral malignancy within the preceding 5 years were excluded. Analysis was by intent-to-treat.Patients were assigned to a control group (n = 641) or to a group undergoing reduction of iron stores by phlebotomy with removal of defined volumes of blood at 6-month intervals (avoiding iron deficiency) (n = 636), stratified by hospital, age, and baseline smoking status, diagnosis of diabetes mellitus, ratio of high-density to low-density lipoprotein cholesterol level, and ferritin level.The primary end point was all-cause mortality; the secondary end point was death plus nonfatal myocardial infarction and stroke.There were no significant differences between treatment groups for the primary or secondary study end points. All-cause deaths occurred in 148 patients (23%) in the control group and in 125 (20%) in the iron-reduction group (hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.67-1.08; P = .17). Death plus nonfatal myocardial infarction and stroke occurred in 205 patients (32%) in the control group and in 180 (28%) in the iron-reduction group (HR, 0.88; 95% CI, 0.72-1.07; P = .20).Reduction of body iron stores in patients with symptomatic PAD did not significantly decrease all-cause mortality or death plus nonfatal myocardial infarction and stroke.Clinicaltrials.gov Identifier: NCT00032357.

Abstract

The informed consent process for research warrants improvement but approaches designed to enhance informed consent need testing in the context of actual clinical research.Test the cumulative effect of a retrospective quality assurance questionnaire intended to enhance awareness in the person obtaining informed consent on the quality of the informed consent in clinical trials.In the Veterans Affairs Cooperative Study 'Enhancing the Quality of Informed Consent- Self Monitoring', 30 study sites are randomly assigned from five clinical trials to either use a new quality assurance questionnaire after each informed consent encounter or the standard process of obtaining informed consent. The quality of informed consent is evaluated using independent telephone interviews of 836 subjects who had given consent to participate in the clinical trials and the authors' study. The main outcome measures are two previously validated scores derived from an independent telephone interview, measuring the overall quality of consent as well as the degree of 'therapeutic misapprehension'. Patients and assessors are blind to the study arm assignment.Subjects report complete (93%) or some (6%) satisfaction with the consent process of the 'parent' clinical trial, and 91% recognize no consequences to non-participation. Concerning the 'primary purpose' of the parent trial, 67% indicate understanding of the research purpose, 41% that the research is to benefit others, while 14% think the research is directed to their own benefit; 60% report no risk to participation and 65% report at least one expects direct benefit. Interviewers assess 77% of subjects as showing full appreciation of the 'voluntariness' of participation. The quality assurance questionnaire do not provide an appreciable effect on the quality of informed consent. Using mixed model methods to account for the group randomization, near zero, non-significant effects have been found for the overall assessment score (-0.034 on a 0-10 point scale, standard error 0.099, P = 0.73) and for the score measuring 'therapeutic misconception' (-0.005 on a 0-5 point scale, standard error 0.137, P = 0.97). Permutation methods yield similar results. Confidence intervals are narrow enough to exclude any clinically important effect.The intervention may work in a more homogeneous patient population, or one that is not sampled. The outcome measurement relies on a short, anonymous, telephone interview (to minimize burden and eliminate bias), but a longer, face-to-face interview may be more sensitive to differences. A 'checklist' tied directly to the outcome measures may show an effect.Despite prior beliefs, a standardized quality assurance tool do not enhance informed consent in actual clinical trials. Future research is needed to rigorously evaluate proposed methods to enhance informed consent prior to widespread introduction.

Abstract

Despite ongoing controversy, there has never been a large-scale, prospective study of the cognitive effects of electroconvulsive therapy (ECT). We conducted a prospective, naturalistic, longitudinal study of clinical and cognitive outcomes in patients with major depression treated at seven facilities in the New York City metropolitan area. Of 751 patients referred for ECT with a provisional diagnosis of a depressive disorder, 347 patients were eligible and participated in at least one post-ECT outcome evaluation. The primary outcome measures, Modified Mini-Mental State exam scores, delayed recall scores from the Buschke Selective Reminding Test, and retrograde amnesia scores from the Columbia University Autobiographical Memory Interview-SF (AMI-SF), were evaluated shortly following the ECT course and 6 months later. A substantial number of secondary cognitive measures were also administered. The seven sites differed significantly in cognitive outcomes both immediately and 6 months following ECT, even when controlling for patient characteristics. Electrical waveform and electrode placement had marked cognitive effects. Sine wave stimulation resulted in pronounced slowing of reaction time, both immediately and 6 months following ECT. Bilateral (BL) ECT resulted in more severe and persisting retrograde amnesia than right unilateral ECT. Advancing age, lower premorbid intellectual function, and female gender were associated with greater cognitive deficits. Thus, adverse cognitive effects were detected 6 months following the acute treatment course. Cognitive outcomes varied across treatment facilities and differences in ECT technique largely accounted for these differences. Sine wave stimulation and BL electrode placement resulted in more severe and persistent deficits.

Abstract

Given the history of treatments to date, and the responses of the patient, what is the best treatment to try next? An ensemble of sequential, multistage rules guiding such adaptive decision making can be described as an ;adaptive treatment strategy (ATS)'. Robins' G-computation can be used for estimation of the mean outcome of an ATS from a ;sequential multiple assignment randomized (SMAR)' trial.To develop a variance estimate for the G-computation formula, based on a sequential analysis of the states and treatments observed in the trial, and compare its properties with those of the ;marginal mean' method described by Murphy, which is based on an estimating equation.We use both mathematical calculation and simulation studies to demonstrate the properties of the G-computation and its sequential variance estimate, including finite-sample bias and coverage.The sequential method is unbiased and more efficient when the variation in intervening states contributes substantially to the variation in final outcome, and when the study can be designed to guarantee full observation of the ATS under study. The method extends to the comparison of two or more ATS.If full observation cannot be guaranteed, the method may have poor finite-sample properties.When the states used to adapt treatment contribute substantially to the outcome, and good design technique can be applied, the sequential method provides more efficient estimation.

Abstract

This manuscript presents working definitions for key clinical course indicators for bipolar disorder, including response, remission, relapse, recurrence, and roughening.A work group of experts in bipolar disorder reviewed prior efforts to define clinical course indicators for unipolar depression and for schizophrenia. Using these efforts as templates, the work group developed consensus operational definitions. The rationale for each of the definitions was a point of time when a treatment decision needed to be made.The group defined response as a 50% reduction in a score from a standard rating scale of symptomatology from an appropriate baseline, regardless of index episode type (manic, depressed, or mixed). In addition, the other pole cannot be significantly worsened during response. Remission was defined as absence or minimal symptoms of both mania and depression for at least 1 week. Sustained remission requires at least eight consecutive weeks of remission, and perhaps as many as 12 weeks. A relapse/recurrence was defined as a return to the full syndrome criteria of an episode of mania, mixed episode, or depression following a remission of any duration. Roughening was defined as a return of symptoms at a subsyndromal level, perhaps representing a prodrome of an impending episode.The work group recommends that all reports of clinical trials in bipolar disorder include results using these definitions. This will introduce standards for such reports. Hopefully, the definitions will be revised and improved over time.

Abstract

To confirm the relationship between plasma osteopontin (OPN) levels and treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients in an expanded study.One hundred forty patients with newly diagnosed HNSCC were enrolled onto this study, 54 previously reported and 86 new patients. Pretreatment plasma OPN levels were assessed in all patients by an enzyme-linked immunosorbent assay method. OPN levels were correlated to treatment outcomes in the new group of patients. Detailed analyses were also performed on the relationship between OPN and tumor control rate, event-free survival (EFS), and postrelapse survival for the entire group.Using a previously defined cut off point of 450 ng/mL, there was a significant correlation between OPN and freedom-from-relapse (P = .047), overall survival (P = .019), and EFS (P = .023) in the new, independent patient cohort (n = 86). Sequence of event analyses using the entire group (N = 140) revealed that OPN was an independent prognostic factor for initial tumor control, EFS in those who have achieved tumor control, and postrelapse survival.In this expanded study, we were able to replicate the prognostic significance of OPN using a predefined cut off point in an independent patient group and demonstrated that plasma OPN is an independent prognostic marker for HNSCC.

Abstract

This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of or=11 (HRSD(17)>or=14) defined relapse.The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps.When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.

Abstract

Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta(1)-adrenergic receptor (beta(1)AR), a beta-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, beta(1)-Arg-389 had respective 2.8 +/- 0.3- and 4.3 +/- 2.1-fold greater agonist-promoted contractility vs. beta(1)-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The beta-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 +/- 80 vs. 115 +/- 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that beta(1)AR-389 variation alters signaling in multiple models and affects the beta-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome.

Abstract

Preliminary evidence suggests that valproate is associated with isolated features of polycystic ovarian syndrome (PCOS), while contradictory data support an association between epilepsy and PCOS. The development of PCOS features after initiation of valproate was therefore examined in women with bipolar disorder using a standardized definition of PCOS.Three hundred women 18 to 45 years old with bipolar disorder were evaluated for PCOS at 16 Systematic Treatment Enhancement for Bipolar Disorder sites. A comparison was made between the incidence of hyperandrogenism (hirsutism, acne, male-pattern alopecia, elevated androgens) with oligoamenorrhea that developed while taking valproate versus other anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium. Medication and menstrual cycle histories were obtained, and hyperandrogenism was assessed.Among 230 women who could be evaluated, oligoamenorrhea with hyperandrogenism developed in 9 (10.5%) of 86 women on valproate and in 2 (1.4%) of 144 women on a nonvalproate anticonvulsant or lithium (relative risk 7.5, 95% confidence interval [CI] 1.7-34.1, p = .002). Oligoamenorrhea always began within 12 months of valproate use.Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism. Monitoring for reproductive-endocrine abnormalities is important when starting and using valproate in reproductive-aged women. Prospective studies are needed to elucidate risk factors for development of PCOS on valproate.

Abstract

With remission now the treatment goal, antidepressant trial duration has increased. However, most patients do not remit and are exposed to prolonged, ineffective treatment.Conditional probabilities and signal detection methodology were contrasted in early detection of nonremitters in three comparator, 12-week antidepressant trials conducted in late- or mid-life depression.The mid- and late-life samples did not differ in rates or time-to-onset of remission or accuracy of early identification of nonremission. Using conditional probabilities, there were marked differences in predictive power depending on the remission criterion. With signal detection methods, sensitivity and specificity of early identification were uniform across the differing medication conditions, remission criteria, and the three studies. By week 6, > or = 60% of ultimate nonremitters were identified, while maintaining a false positive rate < or = 20%.The goals of providing maximal opportunity to achieve remission, while minimizing exposure to ineffective treatment can be satisfied by use of duration adaptive designs (DAD). While use of conditional probabilities has been the traditional method for early detection of nonremitters, this approach is inferior to use of signal detection methods. The findings also contradicted the widely held view that patients with late-life depression require longer treatment duration.

Abstract

A common variant of the adenosine monophosphate deaminase (AMPD)-1 gene (C34T) results in enzymatic inactivity and may increase adenosine in cardiac muscle and confer cardioprotection through ischemic preconditioning.We hypothesized that AMPD1 carriers with ischemic heart failure (HF) in the Beta-Blocker Evaluation of Survival Trial (BEST) might have a relative survival advantage. Patients (n = 1038, 20% black) with ischemic (58%) and nonischemic (42%) HF were followed for an average of 2.0 years for cardiovascular mortality. DNA was purified from blood using phenol/chloroform. Genotyping was performed by polymerase chain reaction with 5' exonuclease chemistry. Differences in survival were assessed by comparing Kaplan-Meier curves with the log-rank test. Genotype frequencies differed by ethnicity (P < .001) but not by disease etiology. AMPD1 genotype did not significantly modify survival in the entire study population (hazard ratio [HR] = 0.91, 95% CI = 0.61-1.37), among ischemics (HR = 0.73, CI = 0.44-1.22, P = .23), or ischemic non-blacks (HR = 0.74, CI = 0.44-1.24, P = .25). Genotype did not modify the effect of bucindolol on mortality.Results of this study failed to confirm a reported survival benefit among HF patients carrying the AMPD1 T-allele. However, further studies in larger, more homogeneous populations should explore the possibility of a modest survival advantage for patients with ischemic HF.

Abstract

To determine whether an intervention focusing clinician attention on drug choice for hypertension treatment improves concordance between drug regimens and guidelines.Cluster-randomized controlled trial comparing an individualized intervention with a general guideline implementation in geographically diverse primary care clinics of a university-affiliated Department of Veterans Affairs healthcare system.Participants were 36 attending physicians and nurse practitioners (16 in the general group and 20 in the individualized group), with findings based on 4500 hypertensive patients. A general guideline implementation for all clinicians, including education about guideline-based drug recommendations and goals for adequacy of blood pressure control, was compared with addition of a printed individualized advisory sent to clinicians at each patient visit, indicating whether or not the patient's antihypertensive drug regimen was guideline concordant. We measured change from baseline to end point in the proportion of clinicians' patients whose drug therapy was guideline concordant.The individualized intervention resulted in an improvement in guideline concordance more than twice that observed for the general intervention (10.9% vs 3.8%, t = 2.796, P = .008). Bootstrap analysis showed that being in the individualized group increased the odds of concordance 1.5-fold (P = .025). The proportion of patients with adequate blood pressure control increased within each study group; however, the difference between groups was not significant.An individualized advisory regarding drug therapy for hypertension given to the clinician at each patient visit was more effective in changing clinician prescribing behavior than implementation of a general guideline.

Abstract

Depression in the elderly patient may present special challenges for the design of clinical treatment trials due to a complex antidepressant treatment history, individual contraindications to certain medications, medical comorbidity, as well as concurrent medications for other medical conditions. The chronic, relapsing, and remitting nature of depression calls for a dynamic, adaptive treatment strategy, matching treatment changes to patient responses. To market a drug successfully in a cost-conscious environment, it also may be necessary to define the unique contribution that a new drug makes to the treatment of patients, in addition to proving that it is efficacious (by comparison to placebo). These issues, although not unique to the elderly, take on greater importance and weight as patient populations age. This article describes 2 innovations in clinical trials design that may help deal with these issues.

Abstract

Anticoagulation (AC) with warfarin reduces the risk of thromboembolism (TE) in a variety of applications, yet despite compelling evidence of the value and importance of high quality AC, warfarin remains underused, and dosing is often suboptimal. Approaches to improve AC quality include (1) an AC service (ACS), which allows the physician to delegate day-to-day details of AC management to another provider dedicated to AC care, and (2) incorporating into the treatment plan patient self-testing (PST) under which, after completing a training program, patients perform their own blood testing (typically, using a finger-stick blood analyzer), have dosage adjustments guided by a standard protocol, and forward test results, dosing and other information to the provider. Studies have suggested that PST can improve the quality of AC and perhaps lower TE and bleed rates. The purpose of Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) #481, "The Home INR Study" (THINRS) is to compare AC management with frequent PST using a home monitoring device to high quality AC management (HQACM) implemented by an ACS with conventional monitoring of prothrombin time by international normalized ratio (INR) on major health outcomes. PST in THINRS involves use of an INR monitoring device that is FDA approved for home use.Sites are VA Medical Centers where the ACS has an active roster of more than 400 patients. THINRS includes patients with atrial fibrillation (AF) and/or mechanical heart valve (MHV) expected to be anticoagulated indefinitely. THINRS has two parts. In Part 1, candidates for PST are evaluated for 2 to 4 weeks for their ability to use home monitoring devices. In Part 2, individuals capable of performing PST are randomized to (1) HQACM with testing every 4 weeks and as indicated for out of range values, medication/clinical changes, or (2) PST with testing every week and as indicated for out of range values, medication/clinical changes. The primary outcome measure is event rates, defined as the percent of patients who have a stroke, major bleed, or die. Secondary outcomes include total time in range (TTR), other events (myocardial infarction (MI), non-stroke TE, minor bleeds), competence and compliance with PST, satisfaction with AC, AC associated quality of life (QOL), and cost-effectiveness. To assess the effect of PST frequency on TTR and other outcomes, at selected sites patients randomized to perform PST are assigned one of three test frequencies (weekly, twice weekly, or once every four weeks).

Abstract

Although informed consent is a critical means of protecting the rights and interests of participants in clinical research, effective and efficient means of evaluating the quality of consent are needed. Having such means will be important to monitoring consent and testing potential improvements in the consent process.To develop and test a practical and general means of evaluating the quality of informed consent for clinical research. Methods We developed and tested the Brief Informed Consent Evaluation Protocol (BICEP), a short telephone-based assessment of informed consent. As soon as patient-participants completed the informed consent process for a participating VA Cooperative Studies Program clinical trial they called an interviewer who administered the BICEP.632 participants completed BICEP, representing eight ongoing studies from 14 VA and one non-VA medical centers across the country. Site coordinators reported little to no difficulty implementing BICEP. The average duration of BICEP was 8.8 minutes (SD 3.6). Overall, patient-participants evaluated the informed consent process positively. A reliable coding system was then developed to analyze the verbatim responses of the final 191 participants. An Informed Consent Aggregate Score (ICAS) had a mean score of 8.23 (SD 1.17) with a range of 0-10, with 10 a perfect score; and a Therapeutic Misconception Aggregate Score (TMAS) had a mean of 1.62 (SD 0.93) with a range of 0-5, with 5 a perfect score.The BICEP is an efficient means of evaluating informed consent that is acceptable to research participants and research personnel. While participants tend to be satisfied with the informed consent process, the BICEP indicates there is room for improvement in the informed consent process for research.

Abstract

The objective of this study was to investigate potential predictors of consistent condom use (CCU), including the influence of hormonal contraception/surgical sterilization (HC/SS).Regression methods were used to predict CCU and other measures of CU among 214 sexually active, 18- to 45-year-old women previously diagnosed with a sexually transmitted infection.CCU was significantly associated with younger age, African American ethnicity, having casual partners, recent HIV testing, condom use self-efficacy, and concern about partner relationship. HC/SS was not significantly associated with the likelihood of CCU, before (HC/SS, 21.3%, non-HC/SS, 25.3%; odds ratio [OR], 0.798; P=0.4914) or after (OR, 1.209; P=0.5995) controlling for confounders (age, ethnicity, casual partners). Controlling for age and ethnicity eliminated initial significant or near-significant inverse associations between HC/SS and 3 alternative measures of interval condom use ("any use," "number of unprotected acts," "proportion condom-protected contacts") and substantially diminished the association between HC/SS and "condom use at last sex."Choice of condom use measure and control of confounding variables can substantially affect results when studying potential predictors of condom use such as HC/SS.

Abstract

The dominant pre-marketing clinical trial in psychopharmacology is a non-equivalence design that randomizes patients to one of three treatments: an accepted standard, the innovation (new drug), or placebo, with the main efficacy comparison being innovation vs placebo. The reasons behind the choice of placebo control in new drug development include anticipated small effect size for active-controlled comparisons and the sufficiency of demonstrated treatment effect (new drug vs placebo) for regulatory approval. These reasons have led to great reliance on placebo control in drug evaluation studies, despite the ethical controversy over the use of placebo when there are known effective standard treatments. While the use of placebo controls has been widely debated, a less considered aspect of the usual placebo-controlled non-equivalence design is the disparity between the decisions that it supports and those that pervade clinical practice. We propose an alternative approach that randomizes one group of patients to an adaptive treatment strategy that exemplifies the adaptive nature of clinical decision-making in the treatment of ongoing mental health disorders. The basic idea is to compare the adaptive strategy, which uses a patient's outcomes to date to determine when to switch from an initial treatment (e.g. an accepted standard) to an alternative (e.g. the new) treatment, to fixed trials of either treatment option. We state the conditions under which the adaptive treatment RCT is attractive to implement and the requirements for doing so.

Abstract

Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent.Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the beta-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the beta-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (P<0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months.In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation beta-blocker.

Abstract

Information technology can support the implementation of clinical research findings in practice settings. Technology can address the quality gap in health care by providing automated decision support to clinicians that integrates guideline knowledge with electronic patient data to present real-time, patient-specific recommendations. However, technical success in implementing decision support systems may not translate directly into system use by clinicians. Successful technology integration into clinical work settings requires explicit attention to the organizational context. We describe the application of a "sociotechnical" approach to integration of ATHENA DSS, a decision support system for the treatment of hypertension, into geographically dispersed primary care clinics. We applied an iterative technical design in response to organizational input and obtained ongoing endorsements of the project by the organization's administrative and clinical leadership. Conscious attention to organizational context at the time of development, deployment, and maintenance of the system was associated with extensive clinician use of the system.

Abstract

Iron accumulates imperceptibly over time in adults because intake exceeds loss and because no physiologic mechanism exists for excreting levels that may be toxic. Levels of stored iron represented by the serum ferritin concentration have been implicated in the pathogenesis of vascular (and other) diseases, but the role of such stored iron remains controversial. Our hypothesis was that reduction in body iron stores to levels typical of children and premenopausal women (corresponding to ferritin levels of approximately 25 ng/mL) would alter morbidity and mortality rates in patients with advanced peripheral vascular disease.A randomized, single-blinded, clinical trial of graded reduction of iron stores by controlled phlebotomy was undertaken in patients with advanced peripheral vascular disease. Details of implementation of the protocol for testing this unusual experimental intervention are reported.A methodology is described for testing the concept that reduction of body iron stores (while avoiding iron deficiency) may alter disease outcomes. This methodology appears to be suitable for further testing to determine whether levels of iron stores presumed to be pathologic contribute to disease initiation or progression.

Abstract

Racial distribution of clinical trial participants is important because results from these studies serve to define evidence-based practice. This report summarizes the experience of the VA Cooperative Studies Program (CSP) in enrolling white, black and Hispanic patients.An analysis of enrollment in randomized controlled trials conducted by VA CSP between 1975 and 2000. A standardized enrollment ratio for each trial was calculated by dividing the observed number of enrolled white patients in the trial by the expected number of eligible white patients based on the proportion of white patients hospitalized at the enrolling VA Medical Centers.138 VA CSP clinical trials were initiated between 1975 and 2000, 83 contained information on race for 71,463 patients. Overall, 76% of enrolled patients were white, 20% were black, and 4% were Hispanic. Based on standardized enrollment ratios, 60 of the 83 trials had 95% confidence intervals that excluded 1.0. Of these, 32 studies enrolled more white patients than expected and 28 enrolled more Black and/or Hispanic patients than expected based on the racial distribution of patients hospitalized at sites involved in the trials. When trials were separated by intervention type, 13 of the 19 trials that had an invasive arm enrolled fewer minority patients than expected. In trials that targeted diseases that affect minority populations to a greater degree than whites (diabetes, hypertension and end stage renal disease), 11 of the 14 trials enrolled more minority patients than expected.There were several trials that enrolled either more or less minority patients than expected based on patients hospitalized at study sites. Trials that included an invasive arm enrolled fewer minority participants than expected. Trials that involve invasive therapies may wish to adopt special recruitment strategies to reach minority populations.

Abstract

The use of placebo in the pediatric age group has come under increasing scrutiny. At the 2002 Annual Meeting of the American Academy of Child and Adolescent Psychiatry, the Academy's Workgroup on Research conducted a research forum. The purpose was to identify challenges and their solutions regarding the use of placebo in randomized controlled trials in pediatric psychopharmacology.Workgroups focused on problems and solutions in five areas: ethics and human subjects, research design and statistics, partnering with consumers, U.S. Food and Drug Administration and pharmaceutical industry perspectives, and psychosocial treatments.In many but not all circumstances, inclusion of a placebo control is essential to meet the scientific goals of treatment outcome research. Innovative research designs; involvement of consumers in planning and implementing research; flexibility by industry, academia, the National Institutes of Health, and regulatory agencies acting in partnership; and concomitant use of evidence-based psychosocial services can and should assist in making placebo-controlled trials acceptable.Properly designed placebo-controlled trials remain necessary, ethical, and feasible.

Abstract

STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments.

Abstract

Clinical management of chronic disease requires a dynamic treatment regime (DTR): rules for choosing the new treatment based on the history of response to past treatments. Estimating and comparing the effects of DTRs from a sample of observed trajectories of treatment and outcome depends on the untestable assumption that new treatments are assigned independently of potential future responses to treatment, conditional on the history of treatments and response to date ("sequential ignorability"). In longitudinal observational studies, sequential ignorability must be assumed, while randomization of dynamic regimes can guarantee it.Using several clinical examples, we describe the simplest randomized experimental designs for comparing DTRs. We begin by considering an initial treatment A and a second treatment B, and discuss how a dynamic treatment regime that starts with A and leads (sometimes) to B, might be compared to either fixed treatment A or B. We also illustrate the problem of finding the optimal sequence of treatments in a DTR, when there are several choices. We describe and contrast two ways of incorporating randomization into studies to compare such regimes: baseline randomization among DTRs versus randomization at the decision points (sequentially randomized designs).We discuss estimation and inference from both baseline randomized and sequentially randomized designs and conclude with a discussion of the differences between the experimental and observational approaches to optimizing and comparing dynamic treatment regimes.

Abstract

The Homocysteine Study (HOST) Veterans Affairs Cooperative Studies Program No. 453, is a prospective, randomized, two arm, double blind study of patients with end stage renal disease (ESRD) or advanced chronic kidney disease (ACKD, defined as an estimated creatinine clearance of 30 ml/min or less). Its primary objective is to determine whether administration of high doses of three vitamins, folic acid, vitamin B6 and vitamin B12, to lower the high plasma homocysteine levels, will reduce all cause mortality. The secondary objectives are to examine whether the treatment lowers the incidence of myocardial infarction, stroke, amputation of a lower extremity, a composite of death and the foregoing three events, the plasma homocysteine level, and, in ESRD patients undergoing hemodialysis, thrombosis of the vascular access. A unique feature of this trial is that after initial evaluation at enrollment and one return visit the follow up is exclusively by phone (or, if necessary, by mail). The subject is contacted every three months throughout the duration of the study from a central location. The study drug is shipped to the patient from a central location rather supplied locally. In a two year enrollment period, 2006 patients are to be enrolled. The duration of the observation period is four to six years. Data will be stored and analyzed at a coordinating center. The study design has the power to detect a reduction in all cause mortality rate of 17%. Issues related to the unique features of the design of this study are discussed.

Abstract

It is not known whether the risk of recurrence declines with time in bipolar disorders and in major depression. This study describes the life-long recurrence risk of bipolar I, bipolar II and major depressive disorders.160 bipolar-I, 60 bipolar-II and 186 depressive patients hospitalised between 1959 and 1963 were followed up every five years from 1965 to 1985. The course prior to the index hospitalisation was assessed in retrospect. The recurrence risk was computed by the multiplicative intensity model (Aalen et al. 1980).The cumulative intensity curves for the transition from states of remission to new episodes remained linear over 30 to 40 years after onset, indicating a constant risk of recurrence over the life-span up to the age of 70 or more. The recurrence risk of bipolar disorders (0.40 episodes per year) was about twice that of depression (0.20 episodes per year); BP-II disorders had only a slightly higher recurrence risk than BP-I disorders. There were no significant gender differences in the course of either bipolar or depressive disorders.If long-term trials confirm its efficacy, these results support lifelong prophylactic treatment of severe types of mood disorders.

Abstract

Individual HIV risk estimates were generated from reported sexual behavior for 1,146 California Latino Couples Study participants (573 couples). These Bernoulli process model-based estimates proved strongly associated with individual sexually transmitted disease history. Mean estimated background risk from sexual contacts other than with their primary partner was substantially lower for the females than the males (1.4 vs. 7.4 per 10,000). After including their chance of infection from each other, mean net estimated risk was higher for the females than the males (9.2 vs. 8.6 per 10,000). Individual background risk was predicted by individual demographic and psychosocial characteristics (females: coefficient of concordance C = 0.84 predicting any (nonzero) risk; adjusted R(2) = 36% predicting level of risk, given any risk; males: C = 0.78; R(2) = 24%). Characteristics of women with higher risk primary partners were also identifiable (C = 0.65; R(2) = 13%). There was no significant negative association between the male partner's background sexual risk and the aggregate infectivity of the woman from him (taking into account the total number of their condom-protected and unprotected acts of different types).

Abstract

For power and sample-size calculations, most practicing researchers rely on power and sample-size software programs to design their studies. There are many factors that affect the statistical power that, in many situations, go beyond the coverage of commercial software programs. Factors commonly known as design effects influence statistical power by inflating the variance of the test statistics. The authors quantify how these factors affect the variances so that researchers can adjust the statistical power or sample size accordingly. The authors review design effects for factorial design, crossover design, cluster randomization, unequal sample-size design, multiarm design, logistic regression, Cox regression, and the linear mixed model, as well as missing data in various designs. To design a study, researchers can apply these design effects, also known as variance inflation factors to adjust the power or sample size calculated from a two-group parallel design using standard formulas and software.

Abstract

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was conceived in response to a National Institute of Mental Health initiative seeking a public health intervention model that could generate externally valid answers to treatment effectiveness questions related to bipolar disorder. STEP-BD, like all effectiveness research, faces many design challenges, including how to do the following: recruit a representative sample of patients for studies of readily available treatments; implement a common intervention strategy across diverse settings; determine outcomes for patients in multiple phases of illness; make provisions for testing as yet undetermined new treatments; integrate adjunctive psychosocial interventions; and avoid biases due to subject drop-out and last-observation-carried-forward data analyses. To meet these challenges, STEP-BD uses a hybrid design to collect longitudinal data as patients make transitions between naturalistic studies and randomized clinical trials. Bipolar patients of every subtype with age >/= 15 years are accessioned into a study registry. All patients receive a systematic assessment battery at entry and are treated by a psychiatrist (trained to deliver care and measure outcomes in patients with bipolar disorder) using a series of model practice procedures consistent with expert recommendations. At every follow-up visit, the treating psychiatrist completes a standardized assessment and assigns an operationalized clinical status based on DSM-IV criteria. Patients have independent evaluations at regular intervals throughout the study and remain under the care of the same treating psychiatrist while making transitions between randomized care studies and the standard care treatment pathways. This article reviews the methodology used for the selection and certification of the clinical treatment centers, training study personnel, the general approach to clinical management, and the sequential treatment strategies offered in the STEP-BD standard and randomized care pathways for bipolar depression and relapse prevention.

Abstract

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) attempts to fill in major clinical information gaps and to evaluate the theoretical principles and clinical beliefs that currently guide pharmacotherapy of major depressive disorder. The study is conducted in representative participant groups and settings using clinical management tools that easily can be applied in daily practice. Outcomes include clinical outcomes and health care utilization and cost estimates. Research findings should be immediately applicable to, and easily implemented in, the daily primary and specialty care practices. This article provides the overall rationale for STAR*D and details the rationale for key design, measurement, and analytic features of the study.

Abstract

Department of Veterans Affairs Cooperative Study 420 is a randomized clinical trial of 2 methods of group psychotherapy for treating posttraumatic stress disorder (PTSD) in male Vietnam veterans.Vietnam veterans (360 men) were randomly assigned to receive trauma-focused group psychotherapy or a present-centered comparison treatment that avoided trauma focus. Treatment was provided weekly to groups of 6 members for 30 weeks, followed by 5 monthly booster sessions. Severity of PTSD was the primary outcome. Additional measures were other psychiatric symptoms, functional status, quality of life, physical health, and service utilization. Follow-up assessments were conducted at the end of treatment (7 months) and at the end of the booster sessions (12 months); 325 individuals participated in 1 or both assessments. Additional follow-up for PTSD severity was performed in a subset of participants at 18 and 24 months.Although posttreatment assessments of PTSD severity and other measures were significantly improved from baseline, intention-to-treat analyses found no overall differences between therapy groups on any outcome. Analyses of data from participants who received an adequate dose of treatment suggested that trauma-focused group therapy reduced avoidance and numbing and, possibly, PTSD symptoms. Dropout from treatment was higher in trauma-focused group treatment. Average improvement was modest in both treatments, although approximately 40% of participants showed clinically significant change.This study did not find a treatment effect for trauma-focused group therapy. The difference between the effectiveness and adequate dose findings suggests the possible value of methods to enhance the delivery of cognitive-behavioral treatments in clinical practice settings.

Abstract

Healthcare utilization (HCU) following a sexually transmitted disease (STD) diagnosis is poorly characterized.The goal was to quantify HCU for new/recurrent STDs and other relevant Ob-Gyn and mental health problems in the 18 months subsequent to an STD diagnosis.We compared HCU between a group of females aged 18 to 45 years who were Kaiser Permanente Medical Program members with a diagnosed STD (n = 1,205) and a medical center- and age group-matched sample of women seen for a non-STD diagnosis in the same time period (n = 4820), with controlling where appropriate for age, medical center, and chronic disease status.An STD diagnosis was associated with significantly greater likelihood of subsequent visits for STDs (relative risk [RR] = 3.8), pelvic inflammatory disease/endometritis (RR = 2.9), candidiasis (RR = 2.0), vaginitis (RR = 2.4), cervical dysplasia (RR = 1.7), menstrual disorders/abnormal bleeding (RR = 1.3), high risk/complicated/ectopic pregnancy (RR = 1.5), and behavioral/mental health problems (RR = 1.3) than for women seen for a non-STD diagnosis.Detrimental sequelae of STDs are reflected in substantially elevated near-term HCU following an STD diagnosis.

Abstract

As part of the National Institute of Mental Health Strategic Plan for Mood Disorders Research effort, the Clinical Trials and Translation Workgroup was asked to define priorities for clinical trials in mood disorders and for research on how best to translate the results of such research to clinical practice settings. Through two face-to-face meetings and a series of conference calls, we established priorities based on the literature to date and what was known about research currently in progress in this area. We defined five areas of priority that cut across developmental stages, while noting that research on adult mood disorders was at a more advanced stage in each of these areas than research on child or geriatric disorders. The five areas of priority are: 1) maximizing the effectiveness and cost-effectiveness of initial (acute) treatments for mood disorders already known to be efficacious in selected populations and settings when they are applied across all populations and care settings; 2) learning what further treatments or services are most likely to reduce symptoms and improve functioning when the first treatment is delivered well, but the mood disorder does not remit or show adequate improvement; 3) learning what treatments or services are most cost-effective in preventing recurrence or relapse and maintaining optimal functioning after a patient's mood disorder has remitted or responded maximally to treatment; 4) developing and validating clinical, psychosocial, biological, or other markers that predict: a) which treatments are most effective, b) course of illness, c) risk of adverse events/tolerability and acceptability for individual patients or well-defined subgroups of patients; 5) developing clinical trial designs and methods that result in lower research costs and greater generalizability earlier in the treatment development and testing process. A rationale for the importance of each of these priorities is provided.

Abstract

The authors provide brief information about the Department of Veterans Affairs (VA) and the Veterans Health Administration, to establish an understanding of this large, multifaceted organization. They then offer an overview of the VA's Office of Research and Development, with particular emphasis on recent and ongoing efforts to enhance protection of the rights of human participants in clinical research. The authors discuss various policies and regulations intended to protect human participants in any type of VA research. The protection of human research participants must be a major concern for all researchers. Patients should be well informed about the scope of the research and what their participation entails, and there should be no question as to the voluntariness of their consent. Making sure that these standards are met for each and every veteran who participates in VA research is of the utmost importance.

Using inverse weighting and predictive inference to estimate the effects of time-varying treatments on the discrete-time hazardSTATISTICS IN MEDICINEDawson, R., Lavori, P. W.2002; 21 (12): 1641-1661

Abstract

We estimate the effects of non-randomized time-varying treatments on the discrete-time hazard, using inverse weighting. We consider the special monotone pattern of treatment that develops over time as subjects permanently discontinue an initial treatment, and assume that treatment selection is sequentially ignorable. We use a propensity score in the hazard model to reduce the potential for finite-sample bias due to inverse weighting. When the number of subjects who discontinue treatment at any given time is small, we impose scientific restrictions on the potentially observable discontinuation hazards to improve efficiency. We use predictive inference to account for the correlation of the potential hazards, when comparing outcomes under different durations of initial treatment.

Abstract

The mapping and sequencing of the human genome promises rapid growth in understanding the genetically influenced mechanisms that underlie human disease. To realize this promise fully, it is necessary to relate genetic information to clinical phenotypes. Genetic tissue banking in clinical studies provides opportunities to analyze the genetic contribution to variation in response to treatments. The challenges to progress are likely to come from the complex organizational, social, political, and ethical issues that must be resolved in order to put clinical and DNA bank information together. Concerns about subjects' rights, informed consent, privacy, and ownership of genetic material require attention in the development of DNA banks. In this paper we describe one approach to the solution of these problems that was adopted by one clinical trials group, the Department of Veterans Affairs Cooperative Studies Program.

Abstract

Predictors for the development of tardive dyskinesia (TD) have been studied extensively over the years, yet there are few studies of predictors of the course of TD after it has developed. Moreover, few studies have examined predictors of the course of other extrapyramidal side effects (EPS) in patients maintained on neuroleptics. The purpose of this study was to determine which modifiable variables are important in the prediction of EPS in patients with persistent TD over a period of as long as 2 years. One hundred fifty-eight patients enrolled in the Veterans Affairs Cooperative Study 394 were included in this study. A linear mixed-effects (LME) analysis to estimate the Abnormal Involuntary Movement Scale score (for TD severity), Simpson-Angus Scale (for parkinsonism severity), and Barnes Akathisia Scale at any given time after intake assessment was performed. The severity of each of the TD and EPS outcomes at any given visit was predicted by their respective baseline severity scores. Additional predictors of a favorable course of TD included lower doses of antipsychotic medications and use of anticholinergic medications. Other predictors of a favorable course of EPS included younger age and the use of atypical antipsychotic medication (for rigidity) and the use of anticholinergic medication (for tremor). These findings indicate that clinician-modifiable factors related to medication usage can influence the outcome of TD and EPS in patients with persistent TD.

Abstract

Over the past 20 years, both inpatient units and outpatient clinics have developed programs for geriatric evaluation and management. However, the effects of these interventions on survival and functional status remain uncertain.We conducted a randomized trial involving frail patients 65 years of age or older who were hospitalized at 11 Veterans Affairs medical centers. After their condition had been stabilized, patients were randomly assigned, according to a two-by-two factorial design, to receive either care in an inpatient geriatric unit or usual inpatient care, followed by either care at an outpatient geriatric clinic or usual outpatient care. The interventions involved teams that provided geriatric assessment and management according to Veterans Affairs standards and published guidelines. The primary outcomes were survival and health-related quality of life, measured with the use of the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), one year after randomization. Secondary outcomes were the ability to perform activities of daily living, physical performance, utilization of health services, and costs.A total of 1388 patients were enrolled and followed. Neither the inpatient nor the outpatient intervention had a significant effect on mortality (21 percent at one year overall), nor were there any synergistic effects between the two interventions. At discharge, patients assigned to the inpatient geriatric units had significantly greater improvements in the scores for four of the eight SF-36 subscales, activities of daily living, and physical performance than did those assigned to usual inpatient care. At one year, patients assigned to the outpatient geriatric clinics had better scores on the SF-36 mental health subscale, even after adjustment for the score at discharge, than those assigned to usual outpatient care. Total costs at one year were similar for the intervention and usual-care groups.In this controlled trial, care provided in inpatient geriatric units and outpatient geriatric clinics had no significant effects on survival. There were significant reductions in functional decline with inpatient geriatric evaluation and management and improvements in mental health with outpatient geriatric evaluation and management, with no increase in costs.

Abstract

Use of coronary angiography after myocardial infarction has been controversial, with some physicians advocating routine use and others advocating selective use only after documentation of residual myocardial ischemia. The effects of these strategies on economic outcomes have not been established.We analyzed data from a randomized, controlled clinical trial conducted in 17 Department of Veterans Affairs hospitals that enrolled 876 clinically uncomplicated patients 24 to 72 hours after an acute non-Q-wave myocardial infarction. The routine invasive strategy included early coronary angiography with revascularization based on established guidelines. The conservative, ischemia-guided strategy included noninvasive testing with radionuclide ventriculography and exercise thallium scintigraphy, followed by coronary angiography in patients with objective evidence of myocardial ischemia. We measured the cost of hospitalization and outpatient visits and tests during follow-up and calculated the incremental cost-effectiveness ratio. The conservative, ischemia-guided strategy had lower costs than the routine invasive strategy, both during the initial hospitalization ($14 733 versus $19 256, P<0.001) and after a mean follow-up of 1.9 years ($39 707 versus $41 893, P=0.04). The hazard ratio for death was 0.72 (confidence limits, 0.51 to 1.01) in the conservative strategy. The conservative strategy had lower costs and better outcomes in 76% of 1000 bootstrap replications, and a cost-effectiveness ratio below $50 000 per year of life added in 96% of replications.A conservative, ischemia-guided strategy of selective coronary angiography and revascularization for patients who develop objective evidence of recurrent ischemia is more cost-effective than a strategy of routine coronary angiography after uncomplicated non-Q-wave myocardial infarction.

Abstract

Although the sophistication and flexibility of the statistical technology available to the data analyst have increased, some durable, simple principles remain valid. Hypothesis-driven analyses, which were anticipated and specified in the protocol, must still be kept separate and privileged relative to the important, but risky data mining made possible by modern computers. Analyses that have a firm basis in the randomization are interpreted more easily than those that rely heavily on statistical models. Outcomes--such as quality of life, symptoms, and behaviors--that require the cooperation of subjects to be measured will come to be more and more important as trials move away from mortality as the main outcome. Inevitably, such trials will have to deal with more missing data, especially because of dropout and noncompliance. There are fundamental limits on the ability of statistical methods to compensate for such problems, so they must be considered when studies are designed. Finally, it must be emphasized that the availability of software is not a substitute for experience and statistical expertise.

Abstract

As psychiatric practice patterns evolve to take advantage of the growing list of treatments with proven efficacy, research studies with broader aims will become increasingly important. Randomized trials may need to accommodate multiple treatment options. In completely randomized designs, patients are assigned at random to one of the options, requiring that patients and clinicians find each of the options acceptable. In "clinician's choice" designs, patients are randomized to a small number of broad strategies and the choice of specific option within the broad strategy is left up to the clinician. The clinician's choice design permits some scope to patient and clinician preferences, but sacrifices the ability to make randomization-based comparisons of specific options. We describe a new approach, which we call the "equipoise stratified" design, that merges the advantages and avoids the disadvantages of the other two designs for clinical trials. The three designs are contrasted, using the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression trial as an example.

Abstract

Accurately predicting Barrett's esophagus (BE) in patients with gastroesophageal reflux disease (GERD) is difficult. Using logistic regression analysis of symptom questionnaire scores we created a model to predict the presence of BE.We conducted a logistic regression analysis of symptom data collected prospectively on 517 GERD patients and created a prediction model based on patient gender, age, ethnicity, and symptom severity.There were 337 (65%) males and 180 (35%) females, of whom 99 (19%) had Barrett's esophagus (BE). Multiple logistic regression analysis was performed to determine the predictive ability of gender, age, and ethnicity along with symptoms of heartburn, nocturnal pain, odynophagia, presence of belching, dysphagia, relief of symptoms with food, and nausea. The only significant predictors (at the 0.05 level) were male gender, heartburn, nocturnal pain, and odynophagia (all with positive effects on the presence of BE) and dysphagia (which had a negative effect). A nomogram was produced to show the effect of a given predictor on the probability of having BE in the context of the effects of the other predictors, and to estimate the probability of having BE for a given individual. The mean score (+/-SD) for the BE patients in our sample was 397.4+/-46.2 with a range of 292-530. For the patients without BE, the mean score (+/-SD) was 351.3+/-60.3 with a range of 190 - 528 (p < 0.001). If screening for BE is performed at a score of 375 or more, our model would have a specificity of 63% with a sensitivity of 77% (95% CI 61-86% given the 63% specificity).By asking seven questions about symptom severity, clinicians may be able to assign a probability to the presence of BE, and thus, determine the need for endoscopy in GERD patients.

Abstract

Although beta-adrenergic-receptor antagonists reduce morbidity and mortality in patients with mild-to-moderate chronic heart failure, their effect on survival in patients with more advanced heart failure is unknown.A total of 2708 patients with heart failure designated as New York Heart Association (NYHA) functional class III (in 92 percent of the patients) or IV (in 8 percent) and a left ventricular ejection fraction of 35 percent or lower were randomly assigned to double-blind treatment with either bucindolol (1354 patients) or placebo (1354 patients) and followed for the primary end point of death from any cause.The data and safety monitoring board recommended stopping the trial after the seventh interim analysis. At that time, there was no significant difference in mortality between the two groups (unadjusted P=0.16). The results presented here are based on complete follow-up at the time of study termination (average, 2.0 years). There were a total of 449 deaths in the placebo group (33 percent) and 411 deaths in the bucindolol group (30 percent; adjusted P=0.13). The risk of the secondary end point of death from cardiovascular causes was lower in the bucindolol group (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99), as was the risk of heart transplantation or death (hazard ratio, 0.87; 95 percent confidence interval, 0.77 to 0.99).In a demographically diverse group of patients with NYHA class III and IV heart failure, bucindolol resulted in no significant overall survival benefit.

Abstract

Posttraumatic stress disorder (PTSD) is a significant problem for a large number of veterans who receive treatment from the Department of Veterans Affairs (VA) health-care system. VA Cooperative Study 420 is a randomized clinical trial of group psychotherapy for treating PTSD among veterans who sought VA care. Participants at ten sites were randomly assigned to receive one of the two treatments: active treatment that embedded exposure therapy in a group context or comparison treatment that avoided trauma focus and instead addressed current interpersonal problems. Treatment was delivered weekly to groups of six participants for 30 weeks, followed by five monthly booster sessions. Follow-up assessments were conducted at the end of treatment (7 months) and the end of boosters (12 months) for all participants. Long-term follow-up data were collected for a subset of participants at 18 and 24 months. The primary outcome is PTSD severity; other symptoms, functional status, quality of life, physical health, and service utilization also were assessed. Data analysis will account for the clustering introduced by the group nature of the intervention. The pivotal comparison was at the end of treatment. Analyses of subsequent outcomes will concentrate on the question of the durability of effects. The study provides an example of how to address the unique challenges posed by multisite trials of group psychotherapy through attention to methodological and statistical issues. This article discusses these challenges and describes the design and methods of the study. Control Clin Trials 2001;22:74-88

Abstract

We wished to determine the effect of post-infarct management strategy on event rates (death or recurrent nonfatal myocardial infarction [MI]) in patients who evolved non-Q-wave MI (NQMI) following thrombolytic therapy.Patients who evolve NQMI following thrombolytic therapy are often considered to be at high risk and are frequently managed with routine early invasive testing despite a lack of data supporting improved outcome.The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study included 115 patients who evolved NQMI following thrombolytic therapy. We compared the event rates in patients randomized to routine early coronary angiography with those in patients randomized to a conservative strategy of noninvasive functional assessment, with angiography reserved for patients with spontaneous or induced ischemia.During an average follow-up of 23 months, 19 of 58 patients (33%) randomized to the invasive management strategy died or suffered recurrent nonfatal MI, compared with 11 of 57 patients (19%) randomized to the conservative strategy (p = 0.152). Equivalent numbers of patients were subjected to revascularization (percutaneous transluminal coronary angioplasty or coronary artery bypass graft). There were more deaths in the invasive management group than in the conservative management group (11 vs. 2). Excess deaths could not be attributed to periprocedural mortality.Overall event rates (death or recurrent nonfatal MI) are comparable with conservative and invasive strategies in patients who evolve NQMI following thrombolytic therapy. Mortality rate in patients managed conservatively is low (3.5%), and routine invasive management may be associated with an increased risk of death.

Abstract

To compare the role of early invasive vs conservative management strategies in treating patients with non-Q wave myocardial infarction with or without a prior myocardial infarction.In patients recovering from non-Q wave myocardial infarction, the prognosis among patients with a first non-Q wave myocardial infarction is significantly better than in patients with a prior myocardial infarction, yet physicians often adopt an early invasive strategy to treat patients with a first non-Q wave myocardial infarction.Non-Q wave myocardial infarction patients enrolled in the VANQWISH trial with a history of prior myocardial infarction were compared to those with a first non-Q wave myocardial infarction, for the trial primary end-point of death or myocardial infarction at 1 and 12 months, as well as for the initial randomized treatment strategy.Of the 920 non-Q wave myocardial infarction patients, 396 had a history of prior myocardial infarction and 524 did not. Patients with a history of prior myocardial infarction were older and had a higher incidence of multiple high-risk baseline characteristics than those with a first non-Q wave myocardial infarction. Compared to the group with a first myocardial infarction, the prior myocardial infarction group suffered more events at both 1 month (11% vs 6%, P=0.007) and at 12 months (29% vs 16%, P<0.001). This difference in outcome remained significant even after adjusting for confounding variables (P<0.0001 at 12 months). Among the non-Q wave myocardial infarction patients with a prior myocardial infarction, the frequency of death or recurrent myocardial infarction was similar in both invasive and conservative groups during the first year of follow-up. Among the first non-Q wave myocardial infarction group, those assigned to the conservative strategy had significantly fewer events (3% vs 9%, P=0.009 at 1 month; 12% vs 20%, P=0.016 at 12 months) and mortality (1% vs 5%, P=0.012 at one month; 5% vs 11%, P=0.009 at 12 months) than those assigned to early invasive strategy.A history of prior myocardial infarction identifies a moderately high-risk subset of non-Q wave myocardial infarction patients who display similar long-term outcomes regardless of the strategy assignment; however, patients with a first non-Q wave myocardial infarction may fare better with a conservative or ischaemia-guided approach during the first post infarction year.

Abstract

This paper derives a formula to calculate the number of deaths required for a proportional hazards regression model with a nonbinary covariate. The method does not require assumptions about the distributions of survival time and predictor variables other than proportional hazards. Simulations show that the censored observations do not contribute to the power of the test in the proportional hazards model, a fact that is well known for a binary covariate. This paper also provides a variance inflation factor together with simulations for adjustment of sample size when additional covariates are included in the model. Control Clin Trials 2000;21:552-560

Abstract

Randomized clinical trial (RCT) results are often difficult to find, interpret, or apply to clinical care. The authors propose that RCTs be reported into electronic knowledge bases-trial banks-in addition to being reported in text. What information should these trial-bank reports contain?Using the competency decomposition method, the authors specified the ideal trial-bank contents as the information necessary and sufficient for completing the task of systematic reviewing.They decomposed the systematic reviewing task into four top-level tasks and 62 subtasks. 162 types of trial information were necessary and sufficient for completing these subtasks. These items relate to a trial's design, execution, administration, and results.Trial-bank publishing of these 162 items would capture into computer-understandable form all the trial information needed for critically appraising and synthesizing trial results. Decision-support systems that access shared, up-to-date trial banks could help clinicians manage, synthesize, and apply RCT evidence more effectively.

Abstract

Multiple treatments are available for nearly all the mood disorders. This range of treatment options adds a new dimension of choice to clinical decision making. In addition to prescribing the best initial treatment, clinicians should have an algorithm for deciding if and when to make subsequent changes in treatment to take advantage of second-line treatment options when necessary. This article aims to 1) show that a wide variety of clinical decisions can be framed as choices among adaptive (within-patient) threshold-based strategies or algorithms, illustrating the generality of the concept; 2) illustrate two ways to design randomized clinical trials to compare treatment strategies with each other to decide which strategy is best; and 3) discuss some of the advantages offered by these designs, in terms of both patient acceptability and adherence to experimental protocols.

Abstract

Because a statistical tie between standard treatment and an innovation is uninterpretable, most trials intended to demonstrate efficacy of innovations in psychopharmacology employ a placebo control group, despite the existence of standard medications for many disorders. In this review I consider the statistical issues that inform the ethics of the decision to use a placebo condition and make the following points: 1) the investigator is relying on the assumption that the effects of delayed standard treatment are neither long-lasting nor harmful; 2) the usual practice of truncating follow-up when a patient ceases to adhere to a study treatment makes it difficult to empirically test that assumption; 3) placebo control trials often suffer from methodological weaknesses (including nonrandom truncation) that reduce their inferential power; 4) these subtleties place a substantial burden on the informed consent process; 5) alternative designs are available but not well explored, due to the dominant role of "regulatory" trial methodology; and 6) researchers should consider other goals besides helping to introduce another treatment that improves on placebos but not the standard treatment.

Abstract

The authors of this study examined multiple recurrences of unipolar major depressive disorder.A total of 318 subjects with unipolar major depressive disorder were prospectively followed for 10 years within a multicenter naturalistic study. Survival analytic techniques were used to examine the probability of recurrence after recovery from the index episode.The mean number of episodes of major depression per year of follow-up was 0. 21, and nearly two-thirds of the subjects suffered at least one recurrence. The number of lifetime episodes of major depression was significantly associated with the probability of recurrence, such that the risk of recurrence increased by 16% with each successive recurrence. The risk of recurrence progressively decreased as the duration of recovery increased. Within subjects, there was very little consistency in the time to recurrence.Major depressive disorder is a highly recurrent illness. The risk of the recurrence of major depressive disorder progressively increases with each successive episode and decreases as the duration of recovery increases.

Abstract

Levels of body iron stores, represented by the serum ferritin concentration, rise with age after adolescence in men and menopause in women. This rise has been implicated mechanistically and epidemiologically in the pathogenesis of atherosclerosis through iron-induced oxygen free radical-mediated lipid oxidation. However, the precise contribution of iron stores to atherosclerosis and its complications are unknown because prospective randomized trials designed to test effects of reduction of iron stores on clinical outcomes in this disease have not been performed.In preparation for a prospective randomized trial, a randomized pilot study was conducted to evaluate the feasibility, safety, and methodologic accuracy of calibrated reduction in iron stores by phlebotomy in a cohort of patients with advanced peripheral vascular disease. Phlebotomy resulted in a significant reduction in serum ferritin concentration to near targeted levels. Thus the formula for calculating the volume of blood to be removed to achieve a predetermined decrement in serum ferritin concentration was accurate and phlebotomy was not associated with any adverse laboratory or clinical effects.Reduction of body iron stores to a predetermined level is feasible and can be achieved in a timely manner with excellent patient compliance. Prospective randomized trials of calibrated reduction of body iron stores may be undertaken to define their pathophysiologic significance in atherosclerosis and other diseases in which excessive iron-induced oxidative stress has been implicated.

Abstract

Several short-term, controlled trials have documented the efficacy of vitamin E in treating tardive dyskinesia. However, the persistent nature of the disease prompted us to perform a multicenter, longer-term trial of vitamin E.The study was a prospective, randomized, 9-site trial of up to 2 years of treatment with d-vitamin E (1600 IU/d) vs matching placebo. One hundred fifty-eight subjects with tardive dyskinesia who were receiving neuroleptic medications were enrolled. The blinded assessments performed were clinical (Abnormal Involuntary Movements Scale, Barnes Akathisia Scale, and Modified Simpson-Angus [for Extrapyramidal Symptoms] Scale) and electromechanical assessments of movement disorders, psychiatric status (Brief Psychiatric Rating Scale), and functioning (Global Assessment of Functioning). There were no significant differences in baseline demographic characteristics or in study assessments between the group that received vitamin E and the group that received placebo.Vitamin E was well tolerated and subject compliance with medication was good and similar between treatment groups. One hundred seven subjects (70% of those receiving vitamin E and 66% of subjects receiving placebo) completed at least 1 year of treatment. There were no significant effects of vitamin E on total scores or subscale scores for the AIMS, electromechanical measures of dyskinesia, or scores from the other 4 scales.This long-term, randomized trial of vitamin E vs placebo found no evidence for efficacy of vitamin E in the treatment of tardive dyskinesia.

Abstract

To compare the incidence of electrocardiographic abnormalities between older (age > or = 70 years) and younger patients presenting with acute non-Q-wave myocardial infarction.Retrospective review of qualifying electrocardiograms in 918 patients enrolled in the multicenter Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study.Seventeen Department of Veterans Affairs medical centers.A total of 918 patients (224 > or = 70 years old) with acute non-Q-wave myocardial infarction.Comparison of electrocardiograms in patients aged > or = 70 years and younger patients for presence of left ventriculary hypertrophy, widened QRS complex, ST and T wave abnormalities, rhythm other than sinus, heart rate > or = 80 beats/minute, and location of acute non-Q-wave myocardial infarction.Left ventricular hypertrophy and ST depression > or = 1 mm were significantly more frequent in older than in younger patients.Older patients presenting with non-Q-wave myocardial infarction have a greater incidence of left ventricular hypertrophy and ST depression on their electrocardiograms than younger patients. Both of these electrocardiographic findings have previously been associated with increased risk of death and recurrent myocardial infarction and may help account for the worse prognosis of non-Q-wave myocardial infarction in older patients.

Abstract

Increased interest in addiction psychopharmacology has raised unique methodologic issues in the design, conduct, and analysis of outcomes in clinical trials of therapeutic agents for drug dependence. This article summarizes issues raised at a meeting in Palo Alto, California, on November 4, 1996, that was sponsored by the Medication Development Division of the National Institute on Drug Abuse and the Department of Veterans Affairs Cooperative Studies Program to discuss the methodologic issues in clinical trials of cocaine pharmacotherapy.

Abstract

Using data from an observational study of affective disorders, we describe the rates of transition among levels of antidepressant treatment for subjects with Major Depressive Disorder (MDD), and relate these changes to changes in clinical status. We report on the treatment received during the first 10 years of follow-up in the Collaborative Depression Study by 555 patients with a diagnosis of MDD of at least one month's duration. This work extends the initial examination of treatment received during the first eight weeks after entry into this study that showed depressed patients to be on low levels of treatment. Multiplicative intensity models which generalize survival analysis models were used to analyse these data. Description of the course of treatment of these depressed patients shows that low levels of treatment persist for these patients across subsequent episodes, and that these episodes, like the index one, are characterized by extended time in a symptomatic subcriterion state after acute symptoms have improved. These long-term descriptions of treatment support the initial hypothesis that these CDS patients were undertreated. The long-term tendency toward undertreatment seems to persist even as newer treatments become available and widely accepted in practice.

Abstract

Practitioners of clinical trials have a responsibility to ensure that patients' participation in research be informed and voluntary. This responsibility implies that we should strive continuously to improve the effectiveness of methods for informing prospective research volunteers about experimental studies, thereby enhancing the protection of their interests. We should test innovations in informed consent in realistic contexts (i.e., in clinical trials) and with randomization, when it is appropriate, at the first opportunity. In this study, we develop a preliminary proposal to improve the quality of informed consent, based on experimentation with informed consent in ongoing clinical trials. We discuss the conceptual, ethical, organizational, and technical bases for such an effort.

Abstract

This multisite study tested the ability of psychophysiological responding to predict posttraumatic stress disorder (PTSD) diagnosis (current, lifetime, or never) in a large sample of male Vietnam veterans. Predictor variables for a logistic regression equation were drawn from a challenge task involving scenes of combat. The equation was tested and cross-validated demonstrating correct classification of approximately 2/3 of the current and never PTSD participants. Results replicate the finding of heightened psychophysiological responding to trauma-related cues by individuals with current PTSD, as well as differences in a variety of other domains between groups with and without the disorder. Follow-up analyses indicate that veterans with current PTSD who do not react physiologically to the challenge task manifest less reexperiencing symptoms, depression, and guilt. Discussion addresses the value of psychophysiological measures for assessment of PTSD.

Abstract

Non-Q-wave myocardial infarction is usually managed according to an "invasive" strategy (i.e., one of routine coronary angiography followed by myocardial revascularization).We randomly assigned 920 patients to either "invasive" management (462 patients) or "conservative" management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia (458 patients), within 72 hours of the onset of a non-Q-wave infarction. Death or nonfatal infarction made up the combined primary end point.During an average follow-up of 23 months, 152 events (80 deaths and 72 nonfatal infarctions) occurred in 138 patients who had been randomly assigned to the invasive strategy, and 139 events (59 deaths and 80 nonfatal infarctions) in 123 patients assigned to the conservative strategy (P=0.35). Patients assigned to the invasive strategy had worse clinical outcomes during the first year of follow-up. The number of patients with one of the components of the primary end point (death or nonfatal myocardial infarction) and the number who died were significantly higher in the invasive-strategy group at hospital discharge (36 vs. 15 patients, P=0.004, for the primary end point; 21 vs. 6, P=0.007, for death), at one month (48 vs. 26, P=0.012; 23 vs. 9, P=0.021), and at one year (111 vs. 85, P=0.05; 58 vs. 36, P= 0.025). Overall mortality during follow-up did not differ significantly between patients assigned to the conservative-strategy group and those assigned to the invasive-strategy group (hazard ratio, 0.72; 95 percent confidence interval, 0.51 to 1.01).Most patients with non-Q-wave myocardial infarction do not benefit from routine, early invasive management consisting of coronary angiography and revascularization. A conservative, ischemia-guided initial approach is both safe and effective.

Abstract

Empirical scores, computerized ST-segment measurements, and equations have been proposed as tools for improving the diagnostic performance of the exercise test.To compare the diagnostic utility of these scores, measurements, and equations with that of visual ST-segment measurements in patients with reduced workup bias.Prospective analysis.12 university-affiliated Veterans Affairs Medical Centers.814 consecutive patients who presented with angina pectoris and agreed to undergo both exercise testing and coronary angiography.Digital electrocardiographic recorders and angiographic calipers were used for testing at each site, and test results were sent to core laboratories.Although 25% of patients had previously had testing, workup bias was reduced, as shown by comparison with a pilot study group. This reduction resulted in a sensitivity of 45% and a specificity of 85% for visual analysis. Computerized measurements and visual analysis had similar diagnostic power. Equations incorporating nonelectrocardiographic variables and either visual or computerized ST-segment measurement had similar discrimination and were superior to single ST-segment measurements. These equations correctly classified 5 more patients of every 100 tested (areas under the receiver-operating characteristic curve, 0.80 for equations and 0.68 for visual analysis; P < 0.001) in this population with a 50% prevalence of disease.Standard exercise tests had lower sensitivity but higher specificity in this population with reduced work-up bias than in previous studies. Computerized ST-segment measurements were similar to visual ST-segment measurements made by cardiologists. Considering more than ST-segment measurements can enhance the diagnostic power of the exercise test.

Abstract

Several studies have found that alpha-tocopherol (vitamin E) can effectively treat tardive dyskinesia (TD). A limitation of these trials is their short treatment durations (maximum of 12 weeks), which do not allow us to address the effects of long-term treatment.To participate, patients had to have TD and be on stable oral medications. The study enrolled 40 patients who received up to 36 weeks of treatment with d-vitamin E (1600 IU per day) or placebo.Using the Abnormal Involuntary Movements Scale (AIMS) score (sum of items #1-7) to measure TD severity, the study found a significant difference (3 points) in mean AIMS scores, in favor of vitamin E, starting at 10 weeks of treatment and continuing through the full 36 weeks. We used linear mixed-effects regression to quantify the impact of several covariates, and found that treatment assignment. TD duration, and chlorpromazine equivalents had significant effects on decreasing the AIMS score.The study's finding that vitamin E is effective in treating TD agrees with results from prior studies and provides evidence that the effect may extend to treatment of up to 36 weeks. These findings are in direct contrast to those of VA Cooperative Study #394, a much larger, long-term, multi-site study, conducted by many of the same investigators, in which Vitamin E was not superior to placebo.

Abstract

This paper analyses data from a large observational study of the course of affective illness to provide insight into the duration and dose of effective maintenance therapies.The data are 236 unipolar patients who had received antidepressants during recovery and were followed for affective recurrence for up to 5 years. Using data on the naturally selected somatic treatments, we have conducted analyses that adjust for the potential confounding effects of prognosis and treatment intensity to estimate the causal effect of level of medication on the course of recurrence.The results of these analyses show that it is important for patients to remain on the level of somatotherapy used to treat the acute episode for the initial 8 months after symptoms have abated. After that time, the rate of recurrence for patients with fewer than five previous episodes is approximately 1% per week or less at all levels of medication (including discontinuation). Patients who had experienced more than several recurrences are at greater risk of recurrence and continue to benefit from any level of medication during the first year after recovery.The CDS analyses reported here suggest that effective maintenance strategies for all but highly recurrent patients may be a middle road, opting for full-dose strategies of limited duration. These results have implications at both the policy and the clinical level, given the need to consider both monetary and nonmonetary costs (side-effects) associated with continued pharmacotherapy during remission.The observational design of the CDS limits the degree to which cause and effect relationships can be inferred from the observed associations.

Abstract

The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial was designed to compare outcomes of patients with a non-Q wave myocardial infarction (NQMI) who were randomized prospectively to an early "invasive" strategy versus an early "conservative" strategy. The primary objective was to compare early and late outcomes between the two strategies using a combined trial end point (all-cause mortality or nonfatal infarction) during at least 1 year of follow-up.Because of the widely held view that survivors of NQMI are at high risk for subsequent cardiac events, management of these patients has become more aggressive during the last decade. There is a paucity of data from controlled trials to support such an approach, however.Appropriate patients with a new NQMI were randomized to an early "invasive" strategy (routine coronary angiography followed by myocardial revascularization, if feasible) versus an early "conservative" strategy (noninvasive, predischarge stress testing with planar thallium scintigraphy and radionuclide ventriculography), where the use of coronary angiography and myocardial revascularization was guided by the development of ischemia (clinical course or results of noninvasive tests, or both).A total of 920 patients were randomized (mean follow-up 23 months, range 12 to 44). The mean patient age was 61 +/- 10 years; 97% were male; 38% had ST segment depression at study entry; 30% had an anterior NQMI; 54% were hypertensive; 26% had diabetes requiring insulin; 43% were current smokers; 43% had a previous acute myocardial infarction; and 45% had antecedent angina within 3 weeks of the index NQMI.Baseline characteristics were compatible with a moderate to high risk group of patients with an NQMI.

Abstract

Useful clinical strategies are adaptive, specifying the sequence of treatments that are alternatives, what it means for the treatment to "work," the rules for abandoning a treatment, and the subsequent treatments. Because combinatorial complexity precludes comparison of every possible whole strategy, current experiment-based methods rely on comparisons among a few options at particularly crucial decision points, and strategies are pieced together from scraps of information. Nonexperimental methods for strategy development offer a seductive alternative, but their advantages may be illusory. Clinical investigators deploy a wide range of study designs to compare treatment strategies in mental health. This article organizes the types of designs by their purpose and annotates this list with comments on the strengths and weaknesses of each type. We conclude with some general comments on the overall process of development of treatment strategies.

Abstract

Some randomized clinical trials of amiodarone therapy to prevent sudden cardiac death have had positive results and others have had negative results, but all were relatively small. This meta-analysis aimed to pool all trials to assess the effect of amiodarone on mortality and the impact of differences in patient population and study design on trial outcomes.Fifteen randomized trials were identified, and outcome measures were combined by use of a random effects model. The effect of patient population and study design on total mortality was assessed by use of a hierarchical Bayes model. Amiodarone reduced total mortality by 19% (confidence limits, 6% to 31%; P

Abstract

Nine VA Medical Centers are participating in a 2-year double-blind placebo controlled study of antioxidant treatment for tardive dyskinesia (TD) conducted by the Department of Veteran Affairs Cooperative Studies Program. One of the principal outcome measures of this study is the score derived from the instrumental assessment of upper extremity dyskinesia. Dyskinetic hand movements are quantified by assessing the variability associated with steady-state isometric force generated by the patient. In the present report, we describe the training procedures and results of a multi-center reliability assessment of this procedure. Data from nine study centers comprising 45 individual patients with six trials each (three from left hand and three from right hand) were reanalyzed by an independent investigator and the results were subjected to reliability assessment. For the statistic of interest (average coefficient of variation over trials 2 and 3 for each hand, then take the larger of these two values), we found very high intraclass correlation coefficients for reliability over all patients across sites (ICC = 0.995). We also calculated the reliability of the measures across trials within patient for each combination of hand (right, left, dominant), rater group (site, control), and trials set (all three, trials 2 and 3). For a given hand and trial set, the reliability of the site raters was similar to that of the control. This study demonstrates that instrumental measures for the assessment of dyskinesia are reliable and can be implemented in multi-center studies with minimal training.

Abstract

This article describes a standardized method for establishing and maintaining desired levels of interrater reliability (IRR) in multicenter trials. The procedure involves six steps: distribution of procedural guides, distribution of an introduction tape, initial distribution of patient interviews to rate, training at the study kickoff meeting, ongoing IRR monitoring, and group training throughout the study. This method is being used in a national Veterans Affairs Cooperative Study (CS #394), involving nine sites to examine the treatment effects of vitamin E on tardive dyskinesia. The six-step standardized process allowed for early detection of areas of concern in assessment administration. When comparing intraclass correlation coefficients (ICCs) at different points in the initial training, the Barnes Akathisia Scale and Anchored Brief Psychiatric Rating Scale reliability improved from 0.68 to 0.74 and from 0.54 to 0.87, respectively. After analyzing the ratings collected prior to the start of CS #394, data were collected to conduct the first check on Abnormal Involuntary Movement Scale (AIMS) IRR during enrollment; the estimated ICC for the AIMS had decreased from 0.87 to 0.60. Raters were instructed to re-assess the subjects from the first videotape on the AIMS and received additional training. The re-rating indicated very good reliability, 0.84, IRR was measured once for the Global Assessment of Functioning Scale resulting in an ICC of 0.90. The companion article (Part II: Edson et al. 1997, page 59 of this issue) describes the statistical procedures used to measure IRR.

Abstract

The present study examined the impact of comorbid major depressive disorder (MDD) on psychiatric morbidity, panic symptomatology and frequency of other comorbid psychiatric conditions in subjects with panic disorder (PD). Four hundred thirty-seven patients with PD were evaluated at intake as part of a multicenter longitudinal study of anxiety disorders; 113 of these patients were also in an episode of MDD. Patients were diagnosed by DSM-III-R criteria utilizing structured clinical interviews. The 113 PD/MDD patients were compared with the 324 remaining PD subjects regarding panic symptoms at intake, sociodemographic, quality of life and psychiatric morbidity variables. Differences in frequency of other comorbid Axis I psychiatric disorders were assessed at intake; personality disorders were evaluated twelve months after intake. The results revealed the PD/MDD patients exhibit increased morbidity and decreased psychosocial functioning as compared to PD patients. Personality disorders were more prevalent in the PD/MDD group at six month follow-up assessment; the PD/MDD group also had an increased frequency of posttraumatic stress disorder (PTSD) and more comorbid Axis I anxiety disorders as compared to the PD group. The total number and frequency of panic symptoms was highly consistent between the two patient groups.

Abstract

The primary goal of Veterans Affairs (VA) Cooperative Study (CS) #394 is to determine if vitamin E is a safe and efficacious treatment for tardive dyskinesia (TD). The study uses various instruments to assess subjects for movement disorders (Abnormal Involuntary Movement Scale [AIMS], and Barnes Akathisia Scale [BAS]), psychopathology (Anchored Brief Psychiatric Rating Scale [BPRS]), and level of functioning (Global Assessment of Functioning scale [GAF]). Since the study involves nine sites, each with its own set of raters, it is important to establish and maintain high interrater reliability (IRR) on these instruments throughout the study and to identify raters who differ significantly from the others. To make this determination, personnel at each site assessed subjects from standardized videotapes on the AIMS, BAS, and Anchored BPRS, and rated written vignettes on the GAF. We fit these data to a two-way additive model to identify nonstandardized raters (i.e., those whose average ratings were significantly lower or higher than the others, or those whose scores, after adjusting for subject and rater effects, were highly variable). The proportion of nonstandardized raters ranged from 7 percent (Anchored BPRS) to 33 percent (AIMS). The estimated intraclass correlation coefficients (ICCs) indicated moderate reliability for the AIMS, BAS, and Anchored BPRS (0.73 to 0.75) and excellent agreement for the GAF (0.90). The companion article (Part I: Tracy et al. 1997, page 53 of this issue) describes the procedures used to train the raters for this study.

Abstract

Tardive dyskinesia (TD) is a frequently occurring side effect of treatment with neuroleptic antipsychotic drugs. TD is a persistent and often irreversible syndrome characterized by abnormal movements, including lingual and orofacial dyskinesia, grimacing, tics, choreic movements of the limbs and trunk, and athetosis and dystonia. In some patients the muscles of respiration and speech may also be involved. There is no established treatment for TD.

Abstract

The authors present a summary scale for assessing the percentage of patients in a large longitudinal study of panic disorder who received proven effective psychopharmacologic treatment. Such a scale provides a means for assessing and comparing somatic treatments of panic disorder across medication classes. The antipanic therapy levels were applied to data on medication treatment received by 492 patients participating in a naturalistic study and reflect psychopharmacologic treatment prescribed in 11 academic centers. Results show that among patients treated by psychiatrists at major teaching hospitals only 54% of the most symptomatic groups received optimal pharmacologic treatment. Among less symptomatic patients, who nonetheless met full criteria for panic disorder with or without agoraphobia, only 43% received maximal therapy.

Abstract

To examine the role of major parental and child diagnostic factors in predicting episodes of serious affective disorder in adolescents in a nonreferred sample.The sample included 139 youngsters (average age 14 years at enrollment) drawn from a health maintenance organization and evaluated at two points in time 4 years apart. Both parents and adolescents were assessed using structured diagnostic instruments scored according to criterion systems. Parent and child lifetime diagnoses identified in the first assessment were used to predict the onset of episodes of serious affective disorder in the adolescents which occurred between the first and second assessment.Stepwise multiple regression analyses of the significant univariate factors showed that the most powerful predictors of episodes of affective disorder were total number of diagnoses the adolescents received prior to first assessment, lifetime duration of parental major depressive disorder, and total number of lifetime nonaffective disorders of the parents.Broad risk factors from different domains best predict episodes of affective disorder in children and adolescents.

Abstract

Previous studies have indicated that genetic investigations of Tourette syndrome (TS) should focus on a phenotype that includes not only TS, but chronic tics (CT) and obsessive-compulsive disorder (OCD) as well. These studies have shown that sex may play a role in determining which of the disorders in the TS spectrum is expressed in a susceptible individual. Female relatives of TS probands far more often express OCD, while male relatives more often express TS or CT. Data from the Yale Family Study of TS were used to model risk to first-degree relatives of probands with TS for a variety of TS disease phenotypes. Risk to relatives was modeled using multivariate Cox regression analysis, a method appropriate for assessing risk when there is correlation among disease onsets. This is the first known application of this method to family data. The study identified two proband characteristics that increase the risk for disease onset among both male and female relatives for all TS spectrum disorders, lending credence to the hypothesis that TS spectrum disorders share a common etiology. These were a relatively younger age-at-onset, and no experience of simple motor tics. The predictive ability of two additional factors varied by both sex and disease phenotype. These characteristics, i.e., proband onset with compulsive tics, and proband onset with range, appear to increase risk primarily in female relatives, and for the OCD part of the spectrum.

Abstract

Clinical trials of drug treatments for psychiatric disorders commonly employ the parallel groups, placebo-controlled, repeated measure randomized comparison. When patients stop adhering to their originally assigned treatment, investigators often abandon data collection. Thus, non-adherence produces a monotone pattern of unit-level missing data, disabling the analysis by intent-to-treat. We propose an approach based on multiple imputation of the missing responses, using the approximate Bayesian bootstrap to draw ignorable repeated imputations from the posterior predictive distribution of the missing data, stratifying by a balancing score for the observed responses prior to withdrawal. We apply the method and some variations to data from a large randomized trial of treatments for panic disorder, and compare the results to those obtained by the original analysis that used the standard (endpoint) method.

Abstract

The current research (1) examines empirical evidence to substantiate the relationship between substance choice and chronology of onset of anxiety and substance use disorders, and (2) provides information on the specificity of substance choice among anxiety disorders. A study group of 181 subjects in the Harvard Anxiety Research Project (HARP) who had a history of substance use disorder were the focus of this examination. Subjects whose anxiety disorder had an onset before their substance use disorder (primary anxiety) were compared with those whose substance use preceded onset of an anxiety disorder (secondary anxiety) for differences in distribution of subjects among categories of substance of abuse. Primary and secondary anxiety groups do not have different ages of onset for substance use disorder, nor was there greater likelihood for choosing alcohol for any of the anxiety disorders. However, there is a decreased risk of alcohol use in the small group of generalized anxiety subjects and an increased risk of opioid use in the small group of posttraumatic stress disorder subjects. There was no indirect support for the self-medication hypothesis. Neither age of onset data, specific substance association, nor proximal diagnosis association support a simple interaction. The strongest finding supported an "avoidance" of CNS stimulants.

Abstract

We sought to determine in a double-blinded, placebo-controlled study if the nonsteroidal anti-inflammatory drug sulindac causes regression of sporadic colonic polyps. The impetus for this study is the profound regressive effect of sulindac on polyps in familial adenomatous polyposis.Asymptomatic patients undergoing routine screening flexible sigmoidoscopy were enrolled if they had polyps of < or = 1 cm in size. Of 162 patients screened, 22 patients were randomly enrolled to take 150 mg of sulindac twice daily, and 22 patients took a placebo. Treatment duration was 4 months and was followed by colonoscopy with removal of all polyps.Four patients were dropped from the study (sulindac group) due to urosepsis (1 patient), heartburn (2 patients), and anemia (1 patient). Compliance (determined by monthly pill counting), mean age, and the effect of sulindac vs. placebo on polyp regression or size were not statistically different in the two treatment groups. Analysis of our data indicated that there is only a 0.8% chance that the probability of polyp regression with sulindac is as large as 50%.Four months of treatment with sulindac does not result in a clinically significant regression of sporadic colonic polyps, although a small effect may not have been detected by the size of our study. Our data suggest that the biological response of sporadic and familial polyposis polyps to sulindac is different.

Abstract

These analyses used a high-intensity follow-up of of patients with bipolar affective disorder to describe the immediate and long-term risks for recurrence and the importance of sustained recovery to those risks. At the baseline evaluation, all patients were in episodes of Research Diagnostic Criteria major depressive disorder, mania or schizoaffective disorder (excluding the mainly schizophrenic subtype); those who were depressed at intake had a history of mania or schizoaffective mania. Raters re-evaluated these patients at 6-month intervals for 5 years and annually for the remainder of a 10-year follow-up. The following report describes relapse risks for the 186 patients observed to recover from their index episodes. Survival analyses quantified the likelihood of relapse over time, beginning after symptom-free periods of 4 months and 1, 2 and 3 years. Further survival analyses used treatment status as a censoring variable to estimate the eventual likelihood of recurrence among those who reported sustained compliance with lithium prophylaxis; the prophylaxis group remained under observation until they relapsed, were lost to follow-up or ceased taking lithium. Progressively longer symptom-free periods were clearly associated with lower relapse risks over the subsequent 4 years. Thereafter, however, this effect dissipitated. 7 years after recovery, the cumulative likelihood of recurrence was four in five for all bipolar patients and two in three for those whose index episode had been followed by at least 3 years without symptoms. Even with sustained lithium prophylaxis, the likelihood of at least one recurrence exceeded 70% within 5 years of recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

An onset cohort of children and adolescents with insulin-dependent diabetes mellitus (IDDM) and their parents were studied. Aspects of family environment were evaluated at study inception, and their influence on the initial level of, and change in, glycemic control over 4 years was examined. Family measures of expressiveness, cohesiveness, and conflict were linked to differences in the longitudinal pattern of glycemic control. In particular, the encouragement to act openly and express feelings directly (expressiveness) seemed to ameliorate deterioration of glycemic control over time in both boys and girls. Boys were especially sensitive to variations in family cohesiveness and conflict; those from more cohesive and less conflicted families showed less deterioration in glycemic control. This study demonstrated the important influence of family psychosocial factors present at diabetes onset on glycemic control in children and adolescents over the first 4 years of IDDM.

Abstract

Clinicians recognize three phases of the treatment of major depression: an acute phase to control disabling symptoms, a continuation phase to avoid relapses of a single episode, and a preventive phase to avoid recurrences of new episodes over time. With no directly measurable trace of the underlying pathological process, the distinction is based arbitrarily on the passage of time in remission. The clinician who has successfully treated a patient with antidepressant medications in the acute phase has a critical clinical decision to make for the continuation and preventive phases: whether to continue to prescribe the medication, for how long, and at what dose. This decision, like most clinical decisions in psychiatry, is not yet completely determined by the results of randomized clinical trials. Only a handful of such trials have been completed, covering just a fraction of the possible maintenance strategies (defined by treatment drop times). For many reasons, observational studies of the outcome of naturally occurring treatment choices play an important supporting role, helping to extend the reach of completed studies and to design new studies. Causal inference from observational studies has usually been considered in the context of a decision among a few fixed alternatives at a single time. The particular causal effect of interest in the maintenance of remission dictates that treatment be studied over remission time. This challenges the causal analysis of the observational study. We present issues arising from assessing temporal treatment effects due to nonrandomized treatment assignment over time. We use data from a large observational study of the course of affective illness, to illustrate an approach to this problem.

Abstract

The purpose of this study was to examine the predictive effect of the clinical activity of patients' alcohol use on the course of major depressive disorder.One hundred seventy-six probands with Research Diagnostic Criteria (RDC) diagnoses of both major depressive disorder and alcoholism were compared to 412 probands with major depressive disorder only by using 10 years of short-interval, prospective follow-up data collected as part of the National Institute of Mental Health Collaborative Depression Study. The course of depression was examined by using intensity analysis to represent transitions between states of major depressive disorder. The effect of patients' RDC alcoholism status on the long-term course of major depressive disorder was examined by stratifying the analyses by three levels of alcoholism--never alcoholic, not meeting criteria for current alcoholism, and current alcoholism.Depressed probands who were either never alcoholic or currently nonactive alcoholic had twice the likelihood of recovery from major depressive disorder than did actively alcoholic depressed probands. The three levels of alcoholism did not differentially predict recurrence of major depressive disorder.These findings provide long-term, empirically derived evidence for the deleterious effect of current alcoholism on recovery from depression. The lack of a differential effect of the three levels of alcoholism on recurrence of major depressive disorder suggests that other factors may have greater predictive value.

Abstract

This article reports on the course of uncomplicated panic disorder and panic with agoraphobia on 309 patients participating in the Harvard/Brown Anxiety Research Project, a prospective longitudinal study of patients with DSM-III-R-defined anxiety disorders. At 1 year, there was a .39 probability of full remission for uncomplicated panic disorder and a .17 probability of full remission for panic disorder with agoraphobia Similar differences in time to remission for these syndromes were still found when criteria for remission were made less stringent. However, even requiring less improvement for remission left a large percentage of subjects in an episode, and for those that remitted, relapse occurred quickly, indicating a chronic and recurrent course of illness. This is the first longitudinal, prospective, naturalistic study on a large cohort of subjects with anxiety disorders to have regular, structured, short-interval follow-up. Our results are consistent with the view that panic disorder has a chronic course with high rates of relapse after remission and longer episodes when agoraphobia is a part of the constellation of symptoms.

Abstract

The validity of rapid cycling as a distinct course modifier for bipolar disorder was assessed by comparing patients with and without a history of rapid cycling (4 or more affective episodes in 12 months) on demographic, clinical, family history, and outcome variables. These data were also used to formulate operational criteria for the modifier.Data on subjects with rapid-cycling (N = 120) and nonrapid-cycling (N = 119) bipolar disorder from four sites were pooled and analyzed by using case-control and historical cohort methods.The rapid-cycling group contained more women and more subjects from higher social classes than the nonrapid-cycling group. Family history did not differ between the groups. The diagnosis had predictive validity in that the rapid-cycling patients had more episodes than the nonrapid-cycling patients during prospective follow-up. The relationship between gender and episode frequency supported the validity of the cutoff point of 4-8 episodes per year. The data regarding whether patients with rapid cycling based on truncated episodes more closely resembled rapid-cycling or nonrapid-cycling patients were equivocal. Patients whose only rapid cycling was associated with antidepressants resembled spontaneously rapid-cycling patients, while the majority of spontaneously rapid-cycling patients also had periods of antidepressant-associated rapid cycling.The validity of rapid cycling as a distinct course modifier for bipolar disorder is supported by differences in gender, prospectively assessed outcome, and perhaps social class between rapid-cycling and nonrapid-cycling patients. The relationship of gender to episode frequency supports the cutoff of 4 or more episodes per year.

Abstract

In an effort to identify features indicative of underlying bipolarity within the unipolar relatives of bipolar probands, we compared unipolar relatives of bipolars with unipolar relatives of unipolars. Using data from the Collaborative Study of the Psychobiology of Depression, we compared a number of demographic and clinical features individually, and then developed a logistic regression model for the differences found. Unipolar relatives of bipolars were somewhat more likely to be male and to have subthreshold bipolar features, and less likely to have panic symptoms. In addition, they had a small but significant decrease in the number of depressive symptoms and a large decrease in all treatment indicators. A multiple logistic regression model for these differences was highly significant, but had limited ability to discriminate between the two groups. These differences are not large enough to effectively discriminate between the groups for the purposes of classification. These particular results may result from a number of factors, most likely the choice of comparison group. Nonetheless, the work demonstrates a potential method for the construction of caseness indices for use in genetic studies of bipolar and other psychiatric disorders.

CAUSES OF DEATH AMONG 936 ELDERLY PATIENTS WITH PURE ANXIETY NEUROSIS IN STOCKHOLM COUNTY, SWEDEN, AND IN PATIENTS WITH DEPRESSIVE NEUROSIS OR BOTH DIAGNOSESCOMPREHENSIVE PSYCHIATRYAllgulander, C., Lavori, P. W.1993; 34 (5): 299-302

Abstract

The survival probability and distribution of causes of death were estimated among all 255 male and 685 female inpatients with "pure" anxiety neurosis in Stockholm County between 1969 and 1986 who had survived until 71 years of age. When controlling for sex, age, time period, and catchment area, we found three determined suicides among the men (v 0.8 expected) and four suicides among the women (v 1.1 expected). The shift in the distribution of causes of death was significant in women (P = .024). There were 55 heart deaths among the men versus 46.1 expected. Among 2,331 patients with depressive neurosis and among 1,641 patients with both anxiety and depressive neuroses, suicides were more common than expected in both elderly men and women.

Abstract

The purpose of this study was to assess the course and outcome of anorexia nervosa and bulimia nervosa at 1 year in a large cohort of women with eating disorders.A prospective, naturalistic, longitudinal design was used to map the course of 225 women with anorexia nervosa, bulimia nervosa, and mixed anorexia and bulimia nervosa. Structured interviews were conducted quarterly. Follow-up data are presented in terms of patterns of recovery, clinical features predictive of time to recovery, and the role of comorbid disorders as fixed predictors.The recovery rate of bulimics was significantly better than that of anorexic or mixed subjects, yet nearly half the anorexic and mixed subjects no longer met full DSM-III-R criteria for at least 8 consecutive weeks during the first year of follow-up. Percent ideal body weight and type of eating disorder were significantly associated with outcome.Our findings suggest that the diagnosis of anorexia nervosa has severe implications.

Abstract

This study explored the effects of parental affective disorder on offspring in a nonreferred health maintenance organization 4 years after initial examination.The sample, average age 18.5 years, included 91% of the 153 youngsters initially studied. The main instruments were structured diagnostic interviews scored according to criterion systems for both parents and children; assessment of the youngsters was blind to the previous assessment.Rates of major depressive disorder were higher in the children of parents with affective disorder (26%) compared with those whose parents had no disorder (10%).Depression and other parental affective disorders, as they occur in the community in parents who often are neither recognized nor treated, are associated with serious affective disorder in offspring. Clinical and preventive approaches for these offspring are needed and should be targeted to all families in which there is serious parental affective disorder, not just those who present for psychiatric treatment.

Abstract

This paper presents findings from a multisite study of 126 subjects meeting DSM-III-R criteria for Panic Disorder who also met criteria for a concurrent Major Depressive Episode, Dysthymia, or Depressive Disorder NOS. The study's primary aim was to discern the influence of varying degrees of depression on the comparative efficacy of alprazolam, imipramine and placebo on anxiety outcomes. A placebo-controlled, double-blind, parallel random assignment design was utilized over a total of 16 weeks. There was no medication effect on panic outcomes. At endpoint, percent of anticipatory anxiety (i.e., time spent worrying about having an anxiety attack) was significantly lower in the patients taking active medications vs. placebo. Phobic measures were significantly improved by alprazolam, vs. both imipramine and placebo early in the study; however, by week 8 both active medications were equally superior to placebo in the reduction of phobic symptoms. In addition, both active medications were significantly more effective than placebo in reducing depression. The same efficacy pattern (i.e., active medications superior to placebo) was observed on measures of general functioning. Importantly, there were no significant interactions observed between medication and presence of major depression on the depression measures, indicating that both alprazolam and imipramine were equally efficacious in treating the depression in patients with panic disorder and major depression. Since the patients enrolled in this study suffered from major depressive disorder in the mild to moderate severity range, these results may not be transferrable to patients with panic disorder and severe major depression.

Abstract

We explored the course of bipolar I illness in 172 probands who were followed up prospectively for up to 5 years. Probands were grouped into three categories based on whether the symptoms of the index episode were only depressed, only manic, or mixed/cycling. Data were available for recovery from the index episode, subsequent relapse, and rates of recovery from the first prospective episode. Pure manic probands had a significantly faster rate of recovery (median, 6 weeks) than the mixed/cycling probands (median, 17 weeks), and the pure depressive probands had an intermediate rate (median, 11 weeks). After 5 years of follow-up the mixed/cycling patients continue to have the lowest cumulative probability of recovery from the index episode. Mixed/cycling probands also had a substantially faster time to relapse after recovery from the index episode compared with pure manic patients. For those patients who relapsed, the mixed/cycling patients had the lowest cumulative probability of recovery from the first prospectively observed episode. The treatment received by these patients is described and there is a discussion of how this treatment may have influenced the findings on course and outcome.

Abstract

Eight hundred and six medical and surgical patients who were hospitalized via the emergency ward were followed over their entire impairment stays and rated in anterograde, double-blind fashion for inpatient incidents (falls, medication errors, other). Injuries were minor but affected 2.2% of admissions, a figure which is strikingly similar to studies in other hospitals. There was a statistical trend toward a higher-than-normal risk of hazardous in-hospital incidents for males age 20 to 40 admitted because of injury and for medically ill females over 60 years old.

Abstract

We used multivariate proportional hazards (Cox) models to investigate the effects of cohort of birth on age of first onset of major depression measured independently at two occasions, about six years apart, in the first degree relatives of probands with major affective illnesses. We estimated the cohort trends in strata defined by sociodemographic and other measures, to see if the cohort trends are the same across strata. Graphical summaries of the trends reveal a generally consistent pattern of increasing rates and earlier age of onset with successive birth cohorts, across all strata examined. The relatives with a divorced parent had a somewhat delayed secular increase, suggesting either a ceiling effect or an interaction of the two risk factors (recent cohort of birth and divorced parents) such that the combined effect is less than the sum of the individual effects. Otherwise, the cohort effect is persistent and ubiquitous in this sample.

Abstract

The objective of this report is to determine whether those patients with panic disorder who have current major depression disorder (MDD) differ from those who do not in terms of demographics, comorbid disorders, severity of illness, nature of symptoms of panic attacks and psychosocial functioning. The sample consisted of 182 patients with current or history of panic disorder measured by standardized interview techniques. For analysis these patients were then divided by presence or absence of current MDD. The two groups were not different in age, sex, or marital status, age of onset, or symptom characteristics of panic attacks. However, patients with MDD were more likely to have Social Phobia and Generalized Anxiety Disorder, been hospitalized, made suicide attempts or gestures, have poorer psychosocial functioning, and currently be experiencing panic with more severe symptoms. These findings are discussed in terms of previous literature in the area.

Abstract

The course of illness of 431 subjects with major depression participating in the National Institute of Mental Health Collaborative Depression Study was prospectively observed for 5 years. Twelve percent of the subjects still had not recovered by 5 years. There were decreasing rates of recovery over time. For example, 50% of the subjects recovered within the first 6 months, and then the rate of recovery declined markedly. Instantaneous probabilities of recovery reflect that the longer a patient was ill, the lower his or her chances were of recovering. For patients still depressed, the likelihood of recovery within the next month declined from 15% during the first 3 months of follow-up to 1% to 2% per month during years 3, 4, and 5 of this follow-up. The severity of current psychopathology predicted the probability of subsequent recovery. Subjects with moderately severe depressive symptoms, minor depression, or dysthymia had an 18-fold greater likelihood of beginning recovery within the next week than did subjects who were at full criteria for major depressive disorder. Many subjects who did not recover continued in an episode that looked more like dysthymia than major depressive disorder.

Abstract

In the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression study, data were collected on 2226 first-degree relatives of 612 probands. A second, "blind" reassessment of all relatives was attempted 6 years after the initial evaluation. We report on a final sample of 1629 relatives assessed twice using the Schedule for Affective Disorders and Schizophrenia-Lifetime version. We summarize methods for using stability of diagnosis to model the relationship between clinical covariates and the probability of being a true case. Moreover, we define an index of caseness that can be used to narrow the criteria for who is a case. Of those positive for major depressive disorder at initial evaluation, 74% were positive (on a lifetime basis) at follow-up (ie, were stable). There is a gradient: 48% of those who had three symptoms and no treatment were stable, compared with 96% of those with eight symptoms and treatment. For major depressive disorder, we found the caseness index for those with lifetime mania more severe than that of nonbipolar patients, with those who had hypomania being intermediate. A hierarchical analysis indicated that bipolar I tends to be diagnosed as schizoaffective-manic across occasions, and vice versa. This is consistent with the prior familial analyses that suggest these two diagnoses be combined into a single bipolar phenotype. The analysis for major depressive disorder indicates that caseness appears to represent quantitative, rather than qualitative, differences, with no natural cutoff to identify distinct subgroups. Finally, we discuss implications including utility in genetic analyses, estimation of incidence or prevalence allowing for diagnostic error, and examination of cohort effects.

Abstract

Current and lifetime psychiatric diagnoses were compared in 229 female patients seeking treatment for current episodes of anorexia nervosa (N = 41), bulimia nervosa (N = 98) and mixed anorexia nervosa and Schizophrenia-Lifetime Version, which was modified to include a section for DSM-III-R eating disorders, the Longitudinal Interval Follow-up Evaluation, and the Structured Interview for DSM-III Personality Disorders. Seventy-three percent of the anorexia nervosa subjects, 60% of the bulimia nervosa subjects, and 82% of the mixed anorexia nervosa and bulimia nervosa subjects had a current comorbid Axis I diagnosis. Major depression was the most commonly diagnosed comorbid disorder. Low rates of alcohol and substances abuse disorder were diagnosed, and personality disorder occurred in a minority of the sample. The subjects with mixed disorder manifested a higher lifetime prevalence of kleptomania than either the anorexics or the bulimics. High levels of comorbidity were noted across the eating disorder samples. Mixed disorder subjects manifested the most comorbid psychopathology and especially warrant further study.

Abstract

In a naturalistic study that assessed the lifetime psychiatric histories of 275 children ascertained independently of diagnostic or treatment-seeking behavior, 38 (14%) of the children had a history of anxiety disorder. Rates of comorbidity of depression and other psychiatric disorders were high. Life table estimates of the duration of illness indicate a more protracted time to recover than expected, because 46% would be ill for at least 8 years. Moreover, of those who recovered from their first episode of anxiety disorder, many had experienced recurrence before interview. After conducting pooled analyses, investigators performed separate analyses for children with separation disorder and overanxious disorder. Median age of onset of these conditions was surprisingly young: 10 years of age for overanxious disorder and 8 years of age for separation disorders.

Abstract

The purpose of this study was to assess the prevalence, reliability, and predictive value of comorbid personality disorders in a large sample of 210 women seeking treatment for anorexia nervosa (N = 31), bulimia nervosa (N = 91), or mixed disorder (N = 88).All subjects were interviewed using the Structured Interview for DSM-III Personality Disorders as part of a longitudinal outcome study of eating disorders currently underway at Massachusetts General Hospital.Of the 210 subjects, 27% had at least one personality disorder; the most commonly observed was borderline personality disorder in 18 subjects (9%). The highest prevalence of personality disorders was found in the anorexia nervosa/bulimia nervosa group at 39%, followed by 22% in the anorexics and 21% in the bulimic sample. We found statistically significant differences regarding the distribution of personality disorders across eating disorder groups. The dramatic personality disorder cluster was differentially distributed across groups; this finding was accounted for by higher rates of borderline personality disorder in the bulimia nervosa and anorexia nervosa/bulimia nervosa groups than in the anorexia nervosa group. The anxious personality disorder cluster was differentially distributed across groups with higher rates in the anorexia nervosa and anorexia nervosa/bulimia nervosa samples. Those subjects with a comorbid personality disorder had a significantly slower recovery rate than those without a comorbid personality disorder.The prevalence of personality disorders is not high in treatment-seeking women with eating disorders compared with previously studied samples. The greatest frequency of comorbid personality disorders is in the anorexia nervosa/bulimia nervosa group; this subset also had longer duration of eating disorder illness and much greater comorbid Axis I psychopathology compared with the rest of the sample. Future studies should address whether personality disorders have predictive value in the long-term course and outcome of eating disorders.

Abstract

Ninety-four patients with bipolar disorder participating in a random-assignment, double-blind, prospective maintenance trial of standard- (0.8 to 1.0 mmol/L) vs low-range (0.4 to 0.6 mmol/L) serum lithium levels were assessed to determine the presence and significance of subsyndromal symptoms during periods of remission and recovery. A significant relationship was found between prescribed serum lithium level and the probability of major affective relapse and the occurrence of subsyndromal symptoms. Patients given lithium carbonate to achieve low-range levels had 2.6 times the risk of major affective relapse as those given lithium for standard-range levels and nearly twice the risk of developing subsyndromal symptoms. Patients given the low-range therapy showed a greater variance in weekly Psychiatric Status Rating measures, and their symptoms were more likely to worsen at any time than were symptoms in their standard-level group counterparts. The first occurrence of subsyndromal symptoms increased the risk of major affective relapse fourfold. Following the onset of subsyndromal symptoms, the patients originally randomized to receive standard-range lithium therapy were still better protected from relapse than were patients randomized to receive low-range lithium treatment. Patients were two times more likely to develop depressive than hypomanic symptoms between acute episodes of illness. However, onset of hypomanic symptoms predicted subsequent major affective relapse twice as strongly as did depressive symptoms. Seventy-six percent of patients who became hypomanic had a major affective relapse, compared with 39% of patients who were subclinically depressed.

Abstract

Four hundred three consecutive injury victims admitted via emergency ward over a 3-month period were tracked with 403 contemporaneous controls with medical illness and blindly assessed for in-hospital accidents. There was a high frequency of "incidents" (n = 161 in 107 patients, mainly falls and medication errors), but injury victim admissions resembled medically ill controls when compared by the Kaplan-Meier method for cumulative probability of occurrence of an in-hospital incident. Accelerated failure/time models using the Weibull method to compute average times from admission to incident showed little difference between groups. Admission type (injury victim vs. control) did not predict psychiatric consultation, incident type, or multiple incidents in hospital. Although the injury group had a larger proportion of males and lower mean age, stratification to control for age and sex did not significantly discriminate injury victims from controls in production of incidents: Over all risk of incidents was random. By studying patients during a hospital stay, the effects of differences in individual environment and drug and alcohol intoxication are largely factored out; under these conditions the predictive effect of a prior injury becomes insignificant. In-hospital injury is associated with host factors long known to promote falls: increasing age, debility-cum-mobility, and central nervous system depressant medication.

Abstract

Help-seeking behaviour for treatment of panic disorder was investigated in the sample of the Cross-National Collaborative Panic Study Second Phase. A total of 1168 patients were entered into this trial in 14 countries. Although there were significant center differences in prior treatment and utilization of health services there were also similarities. Treatment had been provided mainly by general practitioners. Drug treatment consisted mostly of prescription of classical tranquilizers and had a longer duration than treatment by psychotherapy. Patients with agoraphobic avoidance, past major depression and longer duration of illness used medical and psychiatric treatment facilities more intensely. Older and more severely disabled subjects were more frequently treated by medical health care providers and were more likely to receive psychotropic drugs. The results indicate that general practitioners carry an important load in the treatment of panic disorders but may need more information about recent development in pharmacotherapy for this condition.

Abstract

Comorbidity, time to recovery, rate of chronicity, and probability of recurrence following recovery were studied in 51 children diagnosed with attention deficit disorder, conduct disorder, and oppositional defiant disorder. Thirty-three percent of the children had two of the above diagnoses, and one child had all three diagnoses. The mean duration of attention deficit disorder was 8 years up to the time of the interview; the mean duration of oppositional defiant disorder was 4.5 years, and the mean duration of conduct disorder was 3 years. Life-table estimates showed that 14% of the children would not have recovered 15 years after the onset of their disorder. Rates of recurrence were high following recovery from each of these disorders.

Abstract

The HRSD, HRSA, SCL-90 scales were psychometrically investigated in a cross-national sample of patients with varieties of non-psychotic symptoms of anxiety and depression. Across the cultural backgrounds the scores obtained from the original versions of these scales are not sufficient statistics. However, latent structure analysis has identified homogeneous subscales for depression (the HRSD) and for discomfort (an SCL subscale). High concurrent validity was found between the subscales of depression, anxiety and discomfort. In international research, inhomogeneity among scale items can be confounded with group differences which are usually ascribed to drug differences.

Abstract

Seven percent (19 of 275) of children and adolescents not ascertained for seeking treatment received a DSM-III diagnosis of alcohol or drug use disorder. Their entire families were recruited into a research program designed to study the risk to offspring of parental psychopathology. The ages of those diagnosed were between 12 and 18 years. The drug and alcohol use disorders had a mean duration of 2 years, and the adolescents who remitted had a high likelihood of developing subsequent psychopathology. These adolescents also showed high rates of other psychiatric disorders. A high rate of alcoholism was found among their parents.

Abstract

The purpose of the study was to assay monoamines in cerebrospinal fluid (CSF) obtained from the trigeminal cistern of 64 patients with intractable facial pain. The CSF was analyzed for homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), end-product markers of activity for the dopamine, serotonin, and norepinephrine systems, respectively. HVA averaged 121 ng/mL in these facial pain patients, compared to 150 to 550 ng/mL in 10 studies of ventricular brain CSF in assorted psychiatric and pain patients. 5-HIAA averaged 29 to ng/mL in our facial pain patients compared to 60 to 120 ng/mL in nine studies of ventricular brain CSF in assorted psychiatric and neurological patients. Trigeminal cistern CSF MHPG averaged 9 ng/mL, similar to the range of 13 studies of lumbar CSF of assorted psychiatric and pain diagnoses. These results indicate that (1) the electrochemical detection method provides a unique way of accurately measuring nanogram concentrations of multiple monoamines in a little as 0.25 mL of CSF; (2) trigeminal cistern and posterior fossa brain CSF monoamine metabolites reflect a different profile of dopaminergic and serotonergic functioning in these facial pain patients from that previously reported with lumbar CSF measurements of other patients; and (3) trigeminal sensory ganglion or brain dopamine and serotonin systems may be concomitantly dysfunctional in intractable facial pain.

Abstract

Clinical trials methodologists recommend counting all events regardless of adherence to protocol and comparing originally randomized groups. This strict "intent-to-treat" policy implies availability and use of outcome measures taken regardless of adherence to treatment protocol. However, outcome measurement in psychiatry requires the cooperation of the patient, and usually occurs in the context of treatment management. Consequently, the patient's or clinician's decision not to adhere to the treatment protocol may be design or default cause censorship of patient data by early truncation. This disables the analysis "by intent to treat" in the strict sense. Current methods applied to such nonrandomly truncated datasets are unsatisfactory ("last value" analysis, survival analysis) or worse (imputation by last value carried forward). I review the context of clinical experimentation in psychiatry, contrast the state of design and analysis with expert recommendations on general methods, review the current statistical strategies and propose that investigators should try to obtain complete follow-up data on all patients without regard to their adherence to treatment protocol.

Abstract

This report addresses the need for prospective studies of personality disorders, as well as some of the difficulties encountered in longitudinal studies when missing data occur due to subject attrition and variable follow-up intervals. Various statistical methods for handling repeated measurements data are reviewed. Many of these methods are quite complex and require expert statistical skills. A simpler way to handle multivariate data using single-number summary scores is proposed as an alternative which is efficient and more readily understood by professionals in many disciplines. Findings are presented from a prospective study of borderline personality disorder which utilized repeated observations over time. Individual regression models were applied to each subject's repeated measurements to obtain a summary of his or her trend on measures of mood and global functioning. The individual regressions produced separate statistics, slopes summarizing rates of change and intercepts which estimated initial levels of functioning. These summaries were then used in group analyses. Findings indicated that subjects showed mild to moderate impairment in mood and moderate impairment in overall functioning. The individual slopes indicated that little overall change was observed during the 5-year period after initial assessment. Neither presence of borderline diagnosis (definite vs. trait vs. no borderline diagnosis) nor gender predicted initial levels of functioning or rates of change. Further examination of other predictors which may influence longterm outcome, such as history of childhood trauma or presence of schizotypal personality features, is suggested. It is concluded that prospective studies are essential in establishing the validity of personality disorders and in understanding individual variation in outcomes.

Abstract

Data concerning 331 subjects participating in a longitudinal study on anxiety disorders were collected over the first 6 months of the study. Preliminary analyses of somatic treatment according to diagnoses and study site were conducted. The comorbidity of one anxiety disorder with other DSM-III-R diagnoses and other types of anxiety disorders was extensive. Patients with panic disorder received significantly more treatment with a benzodiazepine than patients without panic disorder. Fewer than five percent of the sample were treated with a monoamine oxidase inhibitor. Comorbid depression increased the likelihood of treatment with a newer non-MAOI (non-monoamine oxidase inhibitor), nontricyclic antidepressant. Results suggest a strong effect of treatment site on the pharmacotherapy offered.

THE USE OF CONDITIONAL PROBABILITIES TO EXAMINE AGE PERIOD COHORT DATA - FURTHER EVIDENCE FOR A PERIOD EFFECT IN MAJOR DEPRESSIVE DISORDERJOURNAL OF AFFECTIVE DISORDERSWarshaw, M. G., Klerman, G. L., Lavori, P. W.1991; 23 (3): 119-129

Abstract

There is growing evidence that rates of major depression have been increasing over this century, with successive birth cohorts showing increased lifetime risks and earlier ages of onset. In this paper, we describe and compare onset rates in six birth cohorts of first degree relatives of probands with affective disorders from the NIMH Collaborative Study, using graphs of conditional probabilities of first onset. There is evidence of a period effect and age-period interaction for both men and women.

Abstract

Although knowledge of the long-term course and outcome of bulimia nervosa is critical to the effective management of the bulimic patient, research in this area is still in its infancy. Comparisons between existing outcome studies are complicated by differences in research design and methods, a lingering confusion over the definition of terms such as recovery and relapse, and the possibility of multiple forms of bulimia nervosa with varying outcomes. Nonetheless, these studies agree that bulimia nervosa is a chronic disorder, characterized by high rates of relapse and persistent subclinical symptomatology. Future investigations into the course and outcome of bulimia nervosa should focus on the derivation of a universally acceptable terminology and the identification of clinical and psychosocial variables predicting recovery.

Abstract

In 1988, the MacArthur Foundation Research Network on the Psychobiology of Depression convened a task force to examine the ways in which change points in the course of depressive illness had been described and the extent to which inconsistency in these descriptions might be impeding research on this disorder. We found considerable inconsistency across and even within research reports and concluded that research on depressive illness would be well served by greater consistency in the definition change points in the course of illness. We propose an internally consistent, empirically defined conceptual scheme for the terms remission, recovery, relapse, and recurrence. In addition, we propose tentative operational criteria for each term. Finally, we discuss ways to assess the usefulness of such operational criteria through reanalysis of existing data and the design and conduct of new experiments.

Abstract

The survival probability and causes of death before the age of 70 years were analyzed among 3302 inpatients with "pure" anxiety neurosis in Stockholm County, Sweden, who were tracked in case registries by means of automated record linkage during a 14-year period. When all patients with other psychiatric diagnoses and substance abuse were excluded, and marital status controlled for, there was a significant excess of deaths due to verified and undetermined suicides, ie, nearly one third of all deaths. These unnatural deaths preempted any excess in natural causes before the age of 70 years, such as cardiovascular disease. Treatment policy with regard to the use of anxiolytic drugs was not found to influence mortality. We concluded that the risk of suicide in inpatients before the age of 70 years with anxiety disorders may be as high as that in persons with depression or other diagnoses who require inpatient care.

Abstract

Investigations of bulimia nervosa have focused primarily on adult samples, although bulimia nervosa commonly has its onset in adolescence. Pediatricians are often questioned about its etiology, course, and treatment. In an attempt to provide pediatricians with answers, we integrate findings from recent epidemiological and treatment studies with a clinical report of 18 women who developed bulimia nervosa during their teens and sought treatment at our eating disorders clinic.

DEPRESSION IN CHILDREN AND ADOLESCENTS - NEW DATA ON UNDERTREATMENT AND A LITERATURE-REVIEW ON THE EFFICACY OF AVAILABLE TREATMENTSJOURNAL OF AFFECTIVE DISORDERSKeller, M. B., Lavori, P. W., Beardslee, W. R., Wunder, J., Ryan, N.1991; 21 (3): 163-171

Abstract

This article reports on the treatment received by 38 adolescents during an episode of major depression which had a median duration of 4 months. The one subject who received any pharmacologic treatment was prescribed an antianxiety agent. Sixteen percent received psychotherapy. These results are consistent with evidence from studies of adults indicating that depression is underrecognized and undertreated. An important caveat is that the small sample size limits the generalizability of these findings. Moreover, which medication should be prescribed when a diagnosis of depression is made is not yet known with certainty, as literature reviews indicate that more controlled trials of psychotherapeutic and psychopharmacologic treatments for adolescents with depression are needed to better understand the efficacy of treating depressed adolescents.

Abstract

The relevance of the chronology between panic disorder and avoidance behavior and of an early, medium or late onset of panic disorder was tested. Groups from the sample of the cross-national collaborative panic study (CNCPS) were compared for differences in basic characteristics and for the ability to predict treatment response. Patients who developed avoidance behavior before the full syndrome of panic disorder had less often a full agoraphobia but were not different in their response to treatment. Patients with an early onset of panic disorder suffered more often from agoraphobia. The treatment response was similar in the groups with early, medium or late onset of panic disorder. Neither the chronology between panic disorder and avoidance behavior nor the age of onset of panic disorder predicted outcome in short-term treatment with alprazolam or imipramine.

Abstract

There is evidence that rates of major depression have increased over this century, with successive birth cohorts showing increased lifetime risks and earlier ages of onset. Two memory effects have been considered possible artifactual causes of these trends: age-related forgetting and postdating early episodes. In this study, relatives were reinterviewed six years after study entry using interviewers blind to initial reports. We examined the stability of lifetime diagnoses of MDD and ages of first onset. Older relatives were no more likely than younger ones to lose diagnoses nor to postdate their ages of first MDD onset. This is evidence that memory artifacts are not solely responsible for the observed secular trends.

Abstract

The impact of the avoidance behaviour on the psychopharmacological treatment of panic disorder was explored in the Cross National Collaborative Panic Study (n = 1134 patients); in this double blind randomized trial alprazolam, imipramine and placebo were compared during an 8-week treatment period. Patients with extensive avoidance behaviour (agoraphobia) had the most profit from the active drugs. Counter expectancy these specific drug effects were most pronounced in avoidance behaviour. Active drugs (in particular imipramine) were especially more effective than placebo if the patients presented with associated avoidance behaviour. The results suggest that agoraphobia defines more a particular type of anxiety disorder overlapping with panic disorder than merely a severe state of panic disorder.

Abstract

Cross-sectional and longitudinal findings drawn from a 4-year longitudinal study of an onset cohort of preadolescents and early adolescents with insulin-dependent diabetes and their families are presented. Patient and parent perceptions of the family environment near the time of diagnosis are used to examine patterns of adherence in the first year of illness as well as over the four follow-up years. We found that family conflict, cohesion, and organization were strongly associated with independently rated first-year adherence levels. The strongest predictor of longer term adherence was family conflict, as experienced by the patients. In addition, parents' and youngsters' perceptions of family cohesion predicted improved adherence as well as overall higher levels of patient adherence. The findings are discussed with respect to the clinical implications of discovering those family characteristics that can, shortly after diagnosis, predict short- and long-term adherence. In addition, we present planned investigations intended to further clarify paths from family perceptions to individual diabetes behaviors.

Abstract

An onset cohort of adolescents and children with insulin-dependent diabetes mellitus was studied over a 4-year period. Individual patient psychosocial and demographic factors were assessed at study inception and used to examine aspects of adherence over the follow-up. We found that initial assessment of patient coping (defense level, adaptive strength, and locus of control) and adjustment at study inception were predictive of the level of patient adherence to diabetic regimen over the 4 years of study. Psychosocial variables predicted adherence outcomes independent of patient age. This was found for three domains of adherence, i.e., diet, insulin adjustment, and metabolic monitoring, and for the composite index derived from the separate adherence scales. Preadolescents (ages 9-12) at study entry were more adherent than patients who were already adolescent (ages 13-16) when diagnosed. Using multiple regression, three factors (age, adjustment, ego defense level) accounted for 47% of the variance in adherence. No factors were predictive of change in adherence during the follow-up. Thus, psychosocial characteristics of diabetic children assessed shortly after diagnosis predicted typical or average adherence over a 4-year period. Identification of such characteristics may be useful in developing strategies for intervention early in the course of illness.

Abstract

Fifty-six patients with mania and psychotic features and 14 with schizoaffective disorder, manic type, were followed up with biannual assessments during a 5-year period. Results were treated as they were in an analogous follow-up of patients with psychotic major depression or schizoaffective disorder, depressed type. Patients with schizoaffective mania experienced more morbidity during follow-up than did patients with psychotic mania. Among patients with schizoaffective mania, those with a chronic subtype did far worse than did the others, while the mainly schizophrenic--mainly affective distinction was not predictive. When depressed and manic groups were combined (n = 173), the following baseline variables were significant independent predictors of a sustained delusional outcome: longer duration of the index episode, temporal dissociation between psychotic features and affective symptoms, and impaired adolescent friendship pattern.

Abstract

Prognosis is an important issue among patients who have psychotic features and a depressive syndrome; some have outcomes that suggest diagnostic revisions to schizophrenia, and this has far-reaching implications for treatment. To explore this issue, we used biannual evaluations to follow up 103 such individuals for 5 years. Patients with Research Diagnostic Criteria schizoaffective disorder experienced substantially more morbidity of various sorts than did patients with Research Diagnostic Criteria psychotic major depression. Within the group with schizoaffective disorder, patients with the chronic subtype experienced more morbidity than did those with nonchronic schizoaffective disorder; the mainly affective--mainly schizophrenic distinction had less prognostic significance. Factors that predicted sustained delusions at the end of follow-up were exclusively historical and suggested a poor-outcome prototype patient who is single, was socially impaired as an adolescent, and has a history of schizophrenialike psychotic features temporarily dissociated from affective symptoms.

Abstract

Diagnostic or screening tests are used to help determine whether or not a patient has a certain condition or disease. The ability of a diagnostic test to correctly classify subjects is expressed by the four test characteristics-sensitivity, specificity, predictive value positive, and predictive value negative. This paper describes these characteristics and discusses methods for choosing optimal tests or cutoff points to maximize expected value considering the consequences of incorrect diagnoses. Data drawn from ongoing studies of facial pain are used to illustrate some of these concepts.

Abstract

Expressed emotion (EE) refers to a set of emotional aspects of speech for which ratings have been derived. Seven independent studies have established that higher EE ratings in the relatives of patients with schizophrenia predict higher rates of relapse in these patients and two studies have established an association of higher EE in spouses with relapse of depression in their mate. There are no previous studies of parental EE as a predictor of childhood affective disorder or other disorders not in the schizophrenia spectrum. In this study we investigated the relationship between the level of maternal EE and the incidence of DSM-III affective disorder (major depression or mania or dysthymia), substance abuse, or conduct disorder in 273 children. We found that a higher degree of maternal expressed emotion was associated with a three-fold increase in a child's risk (odds multiplier) for having at least one of the following diagnoses: depressive disorder (major depression or dysthymia), substance abuse, or conduct disorder. This increased risk acts in addition to the increased risk of child diagnosis associated with parental affective illness. Research and clinical implications are discussed.

Abstract

In recent years, lower serum levels have been recommended for maintenance therapy with lithium. We studied 94 patients with bipolar disorder in a randomized, double-blind, prospective trial of two different doses of lithium for maintenance therapy: the "standard" dose, adjusted to achieve a serum lithium concentration of 0.8 to 1.0 mmol per liter, and a "low" dose, resulting in a serum concentration of 0.4 to 0.6 mmol per liter. The group medians of the patients' average serum lithium levels were 0.83 mmol per liter for the patients in the standard-range group and 0.54 mmol per liter for those in the low-range group. Six of 47 patients (13 percent) assigned to receive lithium doses that would produce serum levels in the standard range had relapses while on protocol, as compared with 18 of 47 (38 percent) assigned to the low-dose range. The risk of relapse was 2.6 times higher (95 percent confidence interval, 1.3 to 5.2) among patients in the low-range group than among those in the standard-range group. Side effects, including tremor, diarrhea, urinary frequency, weight gain, and a metallic taste in the mouth, were more frequent in the standard-range group. We conclude that doses resulting in serum lithium levels from 0.8 to 1.0 mmol per liter are more effective in treating bipolar disorder than those that result in lower serum lithium concentrations, although the higher doses are associated with a higher incidence of side effects. Recent findings about the limited nephrotoxicity of lithium, along with our observations, suggest that physicians should attempt to maintain serum lithium levels between 0.8 and 1.0 mmol per liter in most patients with bipolar disorder and that they should attempt to enhance patients' understanding of and compliance with this regimen.

Abstract

To evaluate anticholinergic effects on cognition and other functions, we studied 60 healthy volunteers in a double-blind crossover trial of two antiparkinsonian agents, benztropine and amantadine. Benztropine 4 mg/day, but not amantadine 200 mg/day, impaired free recall and perception of time, and subjects' perception of their own memory impairment was significantly greater with benztropine. Side effects in general were worse with benztropine, particularly such anticholinergic effects as dry mouth and blurred vision, and benztropine decreased measured salivary flow to a significantly greater degree than amantadine. Our findings support the hypothesis that drugs that decrease cholinergic transmission impair storage of new information into long-term memory, but have little effect on retrieval from memory or on tasks involving only immediate memory. Clinically, anticholinergic agents can levy a considerable burden on memory and time perception.

Abstract

This is a report on personality traits associated with the first onset of major depression in a sample of high-risk subjects. The subjects are the first-degree relatives, spouses, and their controls of patients with affective disorders. None of these subjects had any history of mental disorder as of their initial evaluation. In the subsequent six years, 29 subjects had a first onset of major depression. These first onset subjects were compared with 370 subjects who continued to be free of illness during the six-year follow-up. Personality traits were assessed at the initial evaluation (ie, before the onset of depression in subjects with first onset) by means of scales from five self-report inventories. Lower emotional strength and resiliency significantly differentiated the first onset from the never ill group; overall differences were not found on measures of interpersonal dependency or extraversion. Age was a significant predictor of first onset, both alone (younger age predicted first onsets) and in interaction with personality measures. Among younger subjects (17 to 30 years of age), personality variables did not significantly discriminate between the two comparison groups. Among older subjects (31 to 41 years of age), however, decreased emotional strength, increased interpersonal dependency, and increased thoughtfulness were associated with first onset of depression.

Abstract

The clinical course of 289 patients with primary non-bipolar major depression without concurrent alcoholism was compared with that of 79 patients with non-bipolar major depression with concurrent alcoholism. Neither patient group suffered from dysthymia or current drug abuse. Contrary to expectations, the two groups did not differ on time to recovery from the major depression, time to relapse into a subsequent major depression, or various cross-sectional clinical ratings at 2 years. The two groups did differ on psychosocial status. Although they were equally impaired at index, the alcoholism group maintained significantly lower levels of psychosocial functioning throughout the 2-year follow-up period. Interpersonal relation with spouse was particularly worse among the alcoholic group.

Abstract

As part of the National Institute of Mental Health Collaborative Program of Depression study, data were collected on 2,225 first-degree relatives of 612 probands. A subset consisting of 187 families of bipolar patients was made available to participants of Genetic Analysis Workshop 5 (GAW5). A description of these data, including sample sizes, diagnoses, and a summary of published analyses, is given.

Abstract

This article reports on a naturalistic study of the course of illness of 38 children diagnosed as having a current or past episode of major depression out of a sample of 275 children who were selected by a method not related to their psychopathology or treatment-seeking behavior. Assessments of the presence of depression and the course of this disorder were made using structured clinical interviews (DICA and DICA-P) and a criterion-based diagnostic system (DSM-III). Longitudinal methods of data analysis included the use of life tables. The proportion of children depressed for 2 years closely resembles the results found in investigations of children who sought treatment for a psychiatric disorder. The probability of remaining depressed in these children was 21% at 1 year after onset, and 10% at the 2-year point. This parallels the rate of chronicity and the decline in rates of recovery which occur over time in adult depression.

Abstract

The relationship between parental psychopathology and psychiatric disturbance in 153 offspring aged 6-19 was assessed in 81 families randomly selected from a prepaid health plan. Offspring of parents with a history of affective disorders and of parents with non-affective psychiatric disorders had higher rates of psychiatric diagnoses and poorer adaptive functioning than children of parents who had never experienced a psychiatric illness. Offspring whose parents had affective disorder had a rate of affective disorder of 30% compared to a rate of 2% in the rest of the sample. This relationship between parental affective disorder and poor child outcome was observed when the separated and divorced families were removed from the analyses.

Abstract

In studying the risk of affective disorder in children, the investigator must deal with the problem that there are two possible units of analysis: the child and the family. An analysis based on children must take account of the intercorrelation within a sibship to produce correct results, while a family-based analysis makes it difficult to investigate individual characteristics of children that help determine the net risk. A two-stage iterative approach to this problem is proposed, yielding estimates of the effect of family-based factors (parental illness, family social class, marital status of parents) and individual factors (age and sex of child, previous non-affective illness). This technique is applied to a sample of 275 children from 143 families representing a wide range of familial risk for affective disorder. The final family-based model (predicting at least one child with affective disorder in the sibship) indicates a six-fold increase in risk to the child associated with maternal affective disorder (P less than 0.001), a three-fold increase in risk associated with paternal affective disorder (P less than 0.05) and divorce or separation of the biological parents, and a suggestion of increased risk in the highest social class (P = 0.06). The excess sibship risk, due to child factors age, prior anxiety disorder, and prior childhood diagnosis, contributed significantly to the family prediction (P less than 0.001).

Abstract

Family studies of disease incidence often include some subjects who receive a diagnostic evaluation less accurate than that obtained with a standard method. This is particularly true of family studies of mental illness, where the standard is a consensus diagnosis based on both direct interview and corroborating family history from an informant in the family. Family members who are not interviewed have diagnoses based on history alone. Interviewed and uninterviewed relatives differ in several factors that influence the probability of disease, so that interview is not independent of disease. Thus, one cannot use the interview data to estimate the overall rate of illness. Family history-based illness rates may substantially underestimate true rates, so the observed rate in uninterviewed subjects is also a biased estimate. We discuss several models to reduce the bias in estimation of incidence rates. We propose explicit modelling and imputation as alternatives to the implicit assumptions that constitute the basis of the methods in current use. A clinical example involving 4806 relatives of probands with major affective illness illustrates the statistical issues.

Abstract

Forty follow-up studies of anorexia nervosa and bulimia nervosa are reviewed. Data on recovery, relapse, and crossover are presented in addition to data on mortality, weight, eating behavior, menses, psychological functioning, and psychosexual functioning. Predictors of these outcomes are discussed. Guidelines for future research are suggested to decrease the variability that is created by differences in research methodologies and study designs.

IMPROVING THE VALIDITY OF FH-RDC DIAGNOSIS OF MAJOR AFFECTIVE-DISORDER IN UNINTERVIEWED RELATIVES IN FAMILY STUDIES - A MODEL BASED APPROACHJOURNAL OF PSYCHIATRIC RESEARCHLavori, P. W., Keller, M. B., Endicott, J.1988; 22 (4): 249-259

Abstract

Analysis of family history and family study diagnoses of major affective disorder in 4806 relatives of affectively ill probands from the NIMH Collaborative Study of the Psychobiology of Depression (Clinical) suggests that rates of disorder in uninterviewed relatives are greatly underestimated by family history. The implications of these underestimates for family and genetics analyses using the family history method are discussed, and other estimates are developed that have better statistical properties. Using the Model Based Direct Adjustment method, the rate of major affective disorder in all relatives (interviewed and uninterviewed) is estimated to be 32%, compared to 25% by the consensus (standard) method, which uses the Family History-RDC interview with one or more family members to make diagnoses on all uninterviewed relatives. This difference (over ten standard errors) is due to the much higher rate of illness estimated for the uninterviewed relatives (28% compared to 14%). Analysis of the sources of insensitivity of the FH-RDC is used to explain the difference between observed and imputed diagnosis rates.

Abstract

Thirty women who sought treatment at an eating disorders clinic in a general hospital and were diagnosed as having a current episode of bulimia nervosa were followed prospectively to assess the course of eating behaviors and other psychopathology. At intake, all 30 met DSM-III criteria for bulimia nervosa, and 57% met Research Diagnostic Criteria for an affective disorder. After 6 months of followup, 33% had recovered from the bulimic episode, and 24% had recovered from the affective disorder. One subject had recovered from both disorders. In subjects with an affective disorder at intake, the affective disorder had little effect on the time to recovery from bulimia nervosa, and recovery from bulimia nervosa had little effect on the time to recovery from the affective disorder.

Abstract

The Longitudinal Interval Follow-up Evaluation (LIFE) is an integrated system for assessing the longitudinal course of psychiatric disorders. It consists of a semistructured interview, an Instruction booklet, a coding sheet, and a set of training materials. An interviewer uses the LIFE to collect detailed psychosocial, psychopathologic, and treatment information for a six-month follow-up interval. The weekly psychopathology measures ("psychiatric status ratings") are ordinal symptom-based scales with categories defined to match the levels of symptoms used in the Research Diagnostic Criteria. The ratings provide a separate, concurrent record of the course of each disorder initially diagnosed in patients or developing during the follow-up. Any DSM-III or Research Diagnostic Criteria disorder can be rated with the LIFE, and any length or number of follow-up intervals can be accommodated. The psychosocial and treatment information is recorded so that these data can be linked temporally to the psychiatric status ratings.

Abstract

Anticholinergic drugs impair one's ability to learn new material, even at routine clinically used doses. During the trihexyphenidyl phase of this double-blind crossover trial, elderly normal subjects complained of confusion and memory impairment and demonstrated a pattern of deficits in memory function compatible with that previously reported to result from anticholinergic drugs. The subjects neither complained of nor demonstrated memory impairment while taking amantadine, which is believed to exert its pharmacological effects upon extrapyramidal disorders via dopaminergic mechanisms and does not appear to be associated with memory impairment. Anticholinergic drugs should be avoided whenever possible in the elderly and especially in those suffering dementia.

Abstract

The stability of the endogenous subtype of major depressive disorder was examined within individuals across consecutive episodes. The subjects were 119 probands from the NIMH Collaborative Depression Study who experienced at least two episodes of unipolar major depressive disorder within a two-year period of biannual evaluations. Structured data collection methods and Research Diagnostic Criteria were employed. The inter-episode stability of subtype diagnosis was low, never producing a kappa of greater than 0.25. This result was not attributable to threshold for diagnosis, time between episodes, differences in severity, or changes in raters.

Abstract

Analyses of data from the NIMH-CRB Collaborative Depression Study on age at onset of Major Depressive Disorder (MDD) in 1144 directly interviewed siblings of patients with major affective disorder show a strong secular trend toward increased lifetime risk and earlier onset in successive cohorts of birth since 1930. The proportionate increases in the instantaneous probabilities (hazard) of onset of MDD for each one year difference in year of birth were 5% for brothers and 7% for sisters. Age-period-cohort analysis suggests a powerful period effect may be responsible for this secular trend in rates of MDD, with rates of onset for siblings between 15 and 50 years of age doubling between the 1960s and 1970s. Possible artifacts are investigated.

Abstract

This study examines the relationship between borderline personality disorder (BPD) and the use of psychiatric services in a naturalistic follow-up comparison with antisocial personality disorder and bipolar type II affective disorder. In the first follow-up series, borderline psychopathology was associated with higher levels of psychiatric service use (emergency, daycare, and inpatient). Markov analyses indicated that the transition between levels of psychiatric service use followed a stationary, second order process (i.e. the immediate past and current service use, predicted use on the next follow-up, and the relationship did not depend on the point in time examined in the follow-up series). Further, the transition probabilities generated from this model did not depend significantly on diagnosis. Predictions from the Markov model about the cumulative probability that subjects would use the highest level of psychiatric services were tested on a second series of follow-ups on the same subjects 20 months later. The model-based predictions (starting from the observed levels in the first two follow-ups of the second series) clustered into three groups, of high, middle, and low predicted probabilities. The subject group with the lowest predicted likelihood had a cumulative probability of 0.19 for using emergency, daycare, or inpatient hospitalization by 22 months of follow-up, whereas the group with the highest likelihood (containing a disproportionate number of BPD subjects) had a cumulative observed probability of 0.80. The Markov model generated from this second series supported the stationarity of the transition process. BPD subjects began using high levels of psychiatric services, but their transition from one level to another over time followed a process similar to that of non-BPD subjects.

Abstract

We report on the impact of specific indexes of the severity and chronicity of parental depression, measures of familial discord, and demographic variables as predictors of impaired adaptive functioning and psychopathology in children. Seventy-two children and their mothers from 37 families were interviewed in person. At least one biological parent in each family had a depressive disorder but neither parent had a history of mania, schizophrenia, or schizoaffective disorder. Almost every measure of severity and chronicity of depression in the biological parents has a statistically significant association with currently impaired adaptation and the presence of a DSM-III-diagnosed disorder in the children, as do the measures of increased discord among married or separated parents. Depression in the mother is more strongly associated with increased psychopathology in the children than is depression in the father.

Abstract

We found significant differences in time to recovery and rates of chronicity in 155 patients with bipolar illness when the episodes were subtyped into those with manic symptoms alone (pure manic), depressive symptoms alone (pure depressed), or symptoms of depression and mania (mixed or cycling) up to the time of entry into a clinical research study. Most of the patients in all three groups who did not recover received levels of somatotherapy that were generally consistent with current recommendations for intensity of treatment appropriate to each condition. Based on a median follow-up of 18 months, the life-table estimate of the probability of remaining ill for at least one year was 7% for the pure manic patients compared with 32% in patients who entered the study with episodes that were mixed or cycling. Purely depressed patients had a 22% probability of remaining ill, approximating rates found in patients without bipolar illness who have episodes of depression. Different clinical variables were found to predict time to recovery in each of these groups. We propose that this subtyping of episodes may be a clinically useful part of the classification of bipolar disorders.

Abstract

We examined the treatment of 338 patients with nonbipolar major depressive disorders during the first eight weeks after entry into the National Institute of Mental Health-Clinical Research Branch Collaborative Program on the Psychobiology of Depression: Clinical Study. Of the 250 entered as inpatients, 31% received either no antidepressant somatotherapy or very low or unsustained levels, and only 49% received at least 200 mg of imipramine hydrochloride (or its equivalent) for four consecutive weeks. Of these patients, 19% received less than 30 minutes of psychotherapy per week. Among the 88 who entered as outpatients, 29% received no antidepressant somatotherapy; another 24% received very low or unsustained levels; only 19% received at least 200 mg of imipramine hydrochloride or its equivalent for four consecutive weeks. Of these patients, 52% received less than 30 minutes of psychotherapy per week. Only a few clinical factors were found to be predictive of treatment intensity. Very large differences in the amount and type of treatment across the five collaborating university centers do not appear to be related to differences in patient characteristics.

Abstract

The authors report on the course of illness in 101 patients who were in an episode (the "index episode") of major depressive disorder when they entered a clinical research study, recovered from that episode, and then relapsed into a new episode (the "first prospective episode") of the disorder. They found a 22% probability that these patients' first prospective episode would last at least 1 year, similar to the 21% rate of chronicity previously reported for the index episode. A long prior episode, older age, and low family income were found to predict chronicity in the first prospective episode.

Abstract

The authors examine the validity of the diagnosis of major depression in nine children and adolescents assessed as part of a study of offspring of parents who had affective disorders. The authors conclude that these nine children were suffering from valid cases of affective disorder because disruptions in multiple domains of functioning accompanied the major depression. The seriousness of the impairment and the finding that few of these children received any treatment at all strongly suggest the need for a heightened awareness among clinicians about the seriousness of depression in children whose parents have affective disorders.

Abstract

As part of the National Institute of Mental Health-Clinical Research Branch Collaborative Program on the Psychobiology of Depression Clinical Study, 2,289 relatives of 523 probands with affective disorder were interviewed with the Schedule for Affective Disorders and Schizophrenia and diagnosed for major depressive disorder by the Research Diagnostic Criteria. Data were analyzed using life-table and survival methods. The findings suggest a progressive increase in rates of depression in successive birth cohorts through the 20th century and an earlier age at onset of depression in each birth cohort. A predominance of female depressives was found in all birth cohorts but the magnitude of female-male differences fluctuated over the decades. The existence of these trends is reported to stimulate further research. These findings are discussed in terms of possible gene-environment interactions. However, no conclusive causal inferences can be drawn pending further investigation.

Abstract

In the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression, six-month follow-up evaluations are available for 24 patients with schizoaffective disorder (depressed type), 56 with psychotic depression, and 274 with nonpsychotic major depression. Outcome for patients with schizoaffective depression was significantly worse than for patients with nonpsychotic depression. The psychotic depression group held an intermediate position on most outcome measures and on psychosocial measures had outcomes significantly worse than those of the nonpsychotic group. Recovery rates assumed a very similar pattern in another cohort admitted more than 40 years ago and followed up without somatic treatment. Follow-ups of 12, 18, and 24 months are available for proportions of each diagnostic group. Survival curves suggest similar outcomes in psychotic depression and nonpsychotic depression, whereas outcomes in schizoaffective depression remain disparate. These trends together with family history studies suggest that a small proportion of patients with schizoaffective disorder, depressed type, will have a long-term course consistent with schizophrenia. Moreover, these data show that outcome studies of schizoaffective disorder must control for follow-up length and the effects of psychosis per se.

Abstract

Biomedical research uses a wide range of designs applied to problems in laboratory, clinical, and population settings. Whatever the nature of the study, a few key features--such as the admission rule, the method of allocating subjects to treatments, and the use of controls--largely determine the strength of scientific inferences. We used these and other features to classify the 332 Original Articles published in the New England Journal of Medicine during 1978-1979. This classification directs attention to critical aspects of study design and performance and can help in the choice of suitable research approaches and protocols. It emphasizes the critical role of the investigators' intent in performing and analyzing a study, and it alerts readers to important aspects of interpretation. We recommend that authors always report enough detail about their work for readers to apply this or a similar classification. Omission of such detail may limit the interpretation of a research study because a study that cannot be classified has probably been incompletely reported.

Abstract

Sometimes questions of clinical interest can be addressed only by investigations without concurrent controls that are under the supervision of the investigator (internal controls). Such studies nearly always make use of other types of comparisons (external controls), such as historical controls. In this paper we examine studies of clinical treatments that have weak internal controls or lack internal controls, as illustrated by recent examples from the Journal. These studies have a small but important and unique role in clinical investigation. Five interrelated features can add to the strength of such studies: (1) an intent by the investigator, expressed before the study, that the treatment will affect the outcomes reported; (2) planning of the analysis before the data are generated; (3) articulation of a plausible hypothesis before the results are observed; (4) a likelihood that the results would still have been of interest if they had been "opposite" in some sense; and (5) reasonable grounds for generalizing the results from the study subjects to a substantially broader group of patients. In spite of potential pitfalls, carefully selected and reported studies without internal controls can play a substantial part in the acquisition of scientific knowledge.

Abstract

Crossover studies (clinical trials in which each patient receives two or more treatments in sequence) and self-controlled studies (in which each patient serves as his or her own control) can produce results that are statistically and clinically valid with far fewer patients than would otherwise be required. We investigated the use of the crossover design in the 13 crossover studies that appeared in the Journal during 1978 and 1979. We considered the following important features of design and analysis as they applied to these studies: the method by which patients were assigned to initial treatment (only 7 of 13 studies used random assignment); the determination of when to switch treatments (10 of the 13 used a time-dependent rule, and 3 a less appropriate disease-state-dependent rule); blinding of the crossover point (in only 3 of the 13 studies was the crossover point concealed, but in 4 of the remaining 10 concealment was impossible); assessment of the effects of the order of treatments (included in only 1 of the 13 studies); and the use of at least minimally acceptable statistical analysis (11 of the 13 studies had such an analysis). We also report briefly on 28 additional studies of a single treatment each, in which each patient served as his or her own control before or after treatment or both. The scientific issues were much the same as in crossover studies except that self-controlled comparisons of treatments tended to be less precisely designed and conducted and to focus on clinical problems and patient groups that are especially difficult to study.

AFFECTIVE-DISORDERS AND ABO BLOOD-GROUPS - NEW DATA AND A REANALYSIS OF THE LITERATURE USING THE LOGISTIC TRANSFORMATION OF PROPORTIONSJOURNAL OF PSYCHIATRIC RESEARCHLavori, P. W., Keller, M. B., Roth, S. L.1984; 18 (2): 119-129

Abstract

No statistically significant associations were found between ABO blood group distributions and RDC subtype diagnoses in 79 subjects with unipolar (single episode and recurrent) and bipolar major depressive disorder using data from our sample. We discuss methodological issues related to the control samples and choice of statistical methods in the reported studies which have looked for associations between ABO blood types and patients diagnosed as having an affective disorder. After presenting our rationale for employing the logarithm of the cross product ratio (lambda) in place of the more traditionally utilized chi-squared, we used lambda to reanalyze the original data from nine studies in the literature. The individual studies are equivocal on the basic issue of an association between type O blood and bipolar I illness, either compared to controls or to recurrent unipolar patients. The combined (weighted average) measure of association indicates a small but definite association, but statistical analysis of the dispersion of the individual estimates around this combined estimate reveals that the studies have a higher degree of heterogeneity in results than expected by chance. The consequences of this finding are discussed, and possible explanations are offered.

Abstract

Twenty-one percent (20/97) of patients with an episode of major depressive disorder and no history of chronic minor depression who sought treatment at five university medical centers had not recovered after two years of prospective follow-up. The rate of recovery was highest in the three months after entry into the study, with a notable decrease in rate after one year. Most patients who did not recover had severe depressive symptoms throughout the two years of follow-up. Long duration of episode before entry into the study, inpatient hospitalization status at entry, intact marriage, low family income, admitting research center, and a history of nonaffective psychiatric disorders (including alcoholism) predicted a chronic course. The implications of these findings for clinicians, researchers, and public health planners are discussed.

Abstract

After a description of threshold models of familial transmission based on an underlying continuous liability distribution, family data from the NIMH-CRB Collaborative Psychobiology of Depression Program-Clinical are described. No sex differences are found for bipolar illness, whereas female relatives have an increased rate of primary unipolar illness when compared to male relatives. This effect persists when relatives are classified according to recurrence, current illness, onset within the last 10 years, and treatment. Moreover, a cohort effect is present in the data and indicates a sex ratio close to one in the young cohort (less than or equal to 25). We considered the transmission of illness from parent to offspring by using survival analysis to examine the proportion of ill brothers and sisters of probands according to the affection status of parents. A maternal effect is found, with the mother having a greater influence on the liability of offspring of either sex. This is at odds with the notion that males and females have identical liabilities, but females have a lower threshold reflecting acknowledgement of more symptoms, etc. However, the mean difference in liability between the sexes may be due to systematic biological/cultural differences, with parental transmission contributing to variation about their means.

Abstract

High levels of agreement are reported for retrospective assessment of treatment history using the Longitudinal Interval Followup Evaluation Baseline (LIFE Base), a recently developed structured psychiatric interview, in a sample of 47 subjects with a moderate to severe affective disorder. In a paired rater/observer design with interviews conducted at five different research centers, most coefficients of reliability (Kappa) were above 0.91. This is the first published reliability study of treatment data and should be encouraging to practitioners and researchers. Future research aimed at assessing the validity of treatment information obtained from patient records and clinical interviews is recommended.

Abstract

Clinical trials of medical treatments often compare two treated groups or a treated group with a separate but concurrent control group. We have examined a consecutive series of 47 such parallel studies reported in the Journal in 1978-1979, including 35 with random assignment to the treated or control group, to discover how this approach is actually used. A major strength of these studies as a group was the frequent use of randomized treatment assignment. Common problems included lack of sufficient detail about methods of randomization, failure to provide enough detail about patient sources, and insufficient use of multivariate statistical techniques and of statistical modeling. We emphasize the importance of avoiding bias by balancing prognostic factors when assigning patients to treatments, reducing bias by modeling the influence of prognostic factors on response, and increasing precision by modeling. We also advocate the careful consideration of the relevance of a treatment comparison within the study to the external world of clinical practice.

Abstract

Of 316 patients with a major depressive disorder who were followed for between 6 months and 2 years, 80 (25%) had a preexisting chronic minor depression of at least 2 years' duration. The chronic minor depression reduced the apparent effect of the known predictors of recovery and relapse from the major depressive disorder and predicted a very pernicious course for the chronic depression. Furthermore, the longer the patient continued to suffer from a chronic minor depression after recovering from the major depression, the greater the probability that relapse into another major depression would preempt recovery from the chronic depression.

Abstract

Risk of relapse into an affective episode was high in the months immediately after recovery from a major depressive disorder (MDD) in 141 subjects with nonbipolar depression, without a preexisting dysthymic disorder. The probability of relapse then declined steadily during the duration of the follow-up (median follow-up, 62 weeks from recovery). In patients entering the study during their first affective episode, the Research Diagnostic Criteria secondary subtype of MDD and an older age of onset predicted a significantly greater likelihood of relapse. Three or more prior episodes of depression predicted a significantly shorter time to the first and second prospectively observed relapses and, thus, a significantly greater likelihood of subsequent multiple affective episodes.

Abstract

Regression models and life tables were used to describe the phenomenon of recovery from major depressive disorder for 101 patients in a naturalistic study in which treatment was not controlled by the investigators. Time to recovery from the onset of the episode was protracted, as only about 50% of patients recovered by one year. Annual rates of recovery then declined steadily to 28% in the second year, 22% in the third year, and 18% in the fourth year. In contrast, speed of recovery from entry into the study was more rapid, and 63% of patients recovered by four months. The recovery rates were about 20% each month for the first four months and then declined sharply for the remaining months of the one-year follow-up. Several clinical variables were statistically significant predictors of recovery when measured from entry into the study: superimposition of the acute episode on a chronic underlying depression, acuteness of onset of he depression, and severity of depression for the subgroup of patients without superimposed illness.

Abstract

With the use of life tables to describe time while patients were well and subsequent rates of relapse for 75 patients after their recovery from an episodes of major depressive disorder in naturalistic study, a high risk of relapse was detected shortly after recovery. Twenty-four percent of patients relapsed within 12 weeks at risk, and 12% of patients relapsed with four weeks at risk. The presence of an underlying chronic depression and three or more previous affective episodes predicted a statistically significant increase in the rate of relapse. These data were used to develop an exponential model of relapse probability for a subgroup of the study population.

Abstract

We report on the treatment received by 217 patients in the community with a diagnosis of major depressive disorder of at least one month's duration. Only a low proportion of subjects received intensive treatment with antidepressant medication or electroconvulsive therapy, as judged by research standards and current clinical teaching. Specific associations emerge between treatment and several clinical, sociodemographic, and diagnostic variables; however, taken together these variables account for only a small fraction of the variance in treatment received. Even among patient subgroups based on severity and long duration of illness, high proportions did not receive adequate therapeutic trials. Substantial differences are found in treatment across community centers that are not attributable to variation in the clinical characteristics of patients. We conclude that more research is needed to determine how patients and practitioners contribute to this phenomenon of low intensity of somatic treatment.

Abstract

In a test-retest reliability study involving 25 psychiatric patients and 5 professional raters we demonstrate that research clinicians from collaborating institutions are able to achieve good reliability for most areas of the SADS and RDC when assessing psychiatrically ill patients under interview conditions that provide even less data than ideally obtained in the practice of clinical research. We expect greater reliability in the actual use of the SADS/RDC on most items and diagnoses since the SADS is intended to be used in conjunction with information obtained from relatives, friends, and treatment staff to confirm and clarify the judgements made by the raters on the patient interviews. Moreover, we are reassured that the diagnosis of schizo-affective disorders and schizophrenia is protected from the item unreliability found with specific delusions and hallucinations. Similarly, the difficulties in determining the episodic and chronic nature of the present episode does not substantially interfere with making an RDC diagnosis of the current condition. A complex diagnostic interview system such as the SADS and RDC requires multiple complementary techniques to determine reliability. We find that establishing explicit procedures for raters to discuss and categorize the reasons for their disagreements on individual items and diagnoses provides valuable data for understanding reliability problems. This has helped us to identify specific areas of the interview and criteria that require further clarification and more intensive rater training to improve ratings made by interviewers.

Abstract

In this study we assess the reliability of rating past psychiatric symptoms and lifetime diagnoses in a currently ill population using the SADS and RDC. Five raters from different centers interviewed 25 subjects in a short-interval test-retest design. Subjects had a wide diversity of affective and non-affective diagnoses and high levels of manifest psychopathology. Our results demonstrate that it is possible for raters from different research centers to reliably rate lifetime diagnoses and previous symptoms. Two important exceptions to the high reliability are the lifetime diagnoses of hypomania and the recurrent unipolar subtype of major depressive disorder, and we alert clinicians and researchers to be cautious when diagnosing these conditions. We conclude that the next step in measuring reliability should be a long-interval test-retest design with separate interviews conducted at the later assessment, one by the original rater and the other by a blind rater.